JP3257731B2 - Benzodiazepine derivatives with anti-ulcer activity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a benzodiazepine derivative having anti-ulcer activity and a remedy for ulcer containing the same. More particularly, the present invention provides histamine H ₂ receptor antagonists regarding low recurrence rate after ulcer treatment.

[0002]

BACKGROUND OF THE INVENTION Currently, the most common drug for treating peptic ulcer is a histamine H ₂ receptor antagonist (H ₂ B). Representative H ₂ B include cimetidine, ranitidine, roxatidine, famotidine, and nizatidine. H
₂ B is an extremely excellent anti-ulcer agent, have the problem that a high recurrence rate after ulcer healing. Therefore, in the treatment of ulcers, it is an important issue to prevent recurrence after healing as well as to alleviate pain and eliminate ulcers.

[0003] Various factors are thought to be involved in the recurrence of ulcers after H ₂ B treatment. For example, in the clinic,
It is known that the gastrin level in blood increases with suppression of gastric acid secretion by taking H ₂ B.
It is thought to trigger the cause of one ulcer recurrence. 1) acid rebound phenomenon (increase in blood gastrin due to long-term administration of an anti-gastric acid secreting drug, resulting in an increase in ECL cells and parietal cells and an increase in acid secretion); Decreased (due to reduced prostaglandin production and reduced prostaglandin in mucosa). One possible way to prevent the occurrence of these two major causes of ulcer recurrence is to block the action of gastrin at the receptor level. Examples of such a drug having a gastrin blocker effect include those described in JP-A-63-238069. However, at present, there is no clinically applicable H ₂ B that utilizes gastrin receptor antagonism to reduce recurrence after ulcer treatment.

[0004]

Means for Solving the Problems The present inventors have found that H ₂ B has a gastric acid secretion inhibitory effect and is effective in treating ulcers.
Results of intensive studies aimed at providing an anti-ulcer agent having an effect of minimizing recurrence after treatment by blocking blood gastrin elevation associated with the gastric acid secretion inhibitory action at the receptor level. , Formula I:

Embedded image Wherein R ¹ and R ³ are each independently hydrogen, halogen, lower alkyl or lower alkyloxy; R ² is hydrogen or lower alkyl; R ⁴ is a single bond or —CO—;
R ⁵ is an aliphatic heterocyclic ring or —NH—; R ⁶ is an optionally substituted C ₁ -C ₁₅ alkylene or an optionally substituted C ₂ -C ₁₅ alkenylene (provided that The alkylene and alkenylene may be substituted within the groups themselves and / or between those groups and adjacent groups by
One or more groups selected from S and NH may be interposed); R ⁷ is any of the following groups:

Embedded image

Embedded image

Embedded image

Embedded image Benzodiazepine derivative (hereinafter also simply referred to as compound I) or a pharmaceutically acceptable salt thereof has histamine H ₂ receptor antagonism and gastrin receptor antagonism. did.

That is, the present invention provides a compound (I) and a salt thereof,
And an anti-ulcer agent containing them. While all compounds of formula I are useful for the purposes of the present invention, compounds of formula I wherein the definition of formula I is shown below
Is preferred. R ¹ is hydrogen, compounds wherein R ² and R ³ are both lower alkyl; aliphatic heterocyclic ring in R ⁵ is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or dioxanyl, compounds which are particularly piperidinyl; in R ⁶ Alkylene is-
(CH ₂ CH ₂ R ⁸ ) p (CH ₂ ) qR ⁹ (CH ₂ ) r- (where R ⁸ and R ⁹ are each independently a single bond, O, S
Or NH; p is an integer of 0 to 5; q is an integer of 1 to 3; r is an integer of 0 to 2), in which R ⁸ is O, p is 2 or 3, and R ⁹ is a single bond And the alkenylene at R ⁶ is — (CH ₂ —C
^{(R 10) = CH) q-} ( where, R ¹⁰ is hydrogen, hydroxy, methyl, or halogen,; q is a group represented by from 1 represents an integer of 3) compound.

Hereinafter, the present invention will be described in more detail. The terms used in this specification are defined as follows. Lower alkyl means a straight or branched tricks like hydrocarbon group having C ₁ -C _6, methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, hexyl and the like.
Lower alkyloxy means straight-chain or branched alkyloxy having 1 to 6 carbon atoms, for example, methoxy,
Examples include ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. Halogen refers to fluorine, chlorine, bromine and iodine. Aliphatic heterocycle means a 5- to 7-membered ring containing at least one oxygen, sulfur or nitrogen atom arbitrarily selected in the ring, and optionally condensed with a carbocycle or another heterocycle. For example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl and the like are included. C
The ₁ -C ₁₅ alkylene means 1-15 alkylene carbon atoms, specifically, for example, methylene, ethylene, propylene, butylene, pentylene, amylene, hexylene,
Heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene and the like can be mentioned.

Alkenylene in C ₂ -C ₁₅ alkenylene which may have a substituent means alkenylene having 2 to 15 carbon atoms and having one or more double bonds in the chain. Examples of such alkenylene include vinylene,
1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1,3-butadienylene, 1-pentenylene, 2-pentenylene, 3-
Pentenylene, 4-pentenylene, 1,3-pentadienylene, 1,4-pentadienylene, 2,4-pentadienylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene,
1,3-hexadienylene, 1,4-hexadienylene,
1,5-hexadienylene, 2,4-hexadienylene,
2,5-hexadienylene, 3,4-hexadienylene,
3,5-hexadienylene, 1,3,5-hexatrienylene, 1-heptenylene, 2-heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-
Heptenylene, 1,3-heptadienylene, 1,4-heptadienylene, 1,5-heptadienylene, 1,6-heptadienylene, 2,4-heptadienylene, 2,5-heptadienylene, 2,6-heptadienylene, 3,5-heptadienylene, 3,6-heptadienylene, 4,6-heptadienylene, 1,3,5-heptatrienylene, 2,4,
6-heptatrienylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-
Octenylene, 6-octenylene, 7-octenylene,
1,3-octadienylene, 1,4-octadienylene,
1,5-octadienylene, 1,6-octadienylene,
1,7-octadienylene, 2,4-octadienylene,
2,5-octadienylene, 2,6-octadienylene,
2,7-octadienylene, 3,5-octadienylene,
3,6-octadienylene, 3,7-octadienylene,
4,6-octadienylene, 4,7-octadienylene,
5,7-octadienylene, 1,3,5-octatrienylene, 1,3,6-octatrienylene, 1,3,7-octatrienylene, 1,4,6-octatrienylene,
4,7-octatrienylene, 1,5,7-octatrienylene, 2,4,6-octatrienylene, 2,4,7-octatrienylene, 2,5,7-octatrienylene,
1,3,5,7-octatetraenylene, 1-nonenylene, 2-nonenylene, 3-nonenylene, 4-nonenylene, 5-nonenylene, 6-nonenylene, 7-nonenylene, 8-nonenylene, 1,3-nonadienylene 1,4-
Nonadienylene, 1,5-nonadienylene, 1,6-nonadienylene, 1,7-nonadienylene, 1,8-nonadienylene, 2,4-nonadienylene, 2,5-nonadienylene, 2,6-nonadienylene, 2,7-nonadienylene,
2,8-nonadienylene, 3,5-nonadienylene, 3,
6-nonadienylene, 3,7-nonadienylene, 3,8-
Nonadienylene, 4,6-nonadienylene, 4,7-nonadienylene, 4,8-nonadienylene, 5,7-nonadienylene, 5,8-nonadienylene, 6,8-nonadienylene, 1,3,5-nonadienylene, 1,3, 6-nonatrienylene, 1,3,7-nonatrienylene, 1,3,8-nonatrienylene, 1,4,6-nonatrienylene, 1,4,
7-nonatrienylene, 1,4,8-nonatrienylene,
1,5,7-nonatrienylene, 1,5,8-nonatrienylene, 1,6,8-nonatrienylene, 2,4,6-nonatrienylene, 2,4,7-nonatrienylene, 2,4,8-
Nonatrienylene, 2,5,7-nonatrienylene, 2,
5,8-nonatrienylene, 2,6,8-nonatrienylene, 3,5,7-nonatrienylene, 3,5,8-nonatrienylene, 3,6,8-nonatrienylene, 4,6,8-nonatrienylene, 1,3, 5,7-nonatetraenylene and 2,4,6,8-nonatetraenylene and the like can be mentioned. The alkylene and alkenylene may be substituted with one or more substituents selected from halogen, lower alkyl and the like. Preferred substituents are halogen. Further, when a hetero atom is interposed at any position in the alkylene or alkenylene chain, -CH ₂ -is -O-,-
S-, -NH- and -CH = or = CH- are -N = and =
Change to N-.

The present invention includes all salts which can be formed with the compounds of the formula I. Generally, it can form a salt with an organic or inorganic acid or an organic or inorganic base, for example,
Examples of the inorganic base include alkali metals (such as sodium and potassium) and alkaline earth metals (such as calcium and magnesium). Examples of the organic base include trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzylethylenediamine , Ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine, and the like, for example, as an inorganic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and as an organic acid, for example, formic acid, acetic acid, trifluoroacetic acid, Oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.Examples of the basic or acidic amino acids include arginine, lysine, ornithine, aspartic acid, gluta Minic acid or the like is used, and a salt with an inorganic acid or a salt with an inorganic base is particularly preferable. Also,
Without being limited to the above examples, the compound of the present invention is a pharmaceutically or pharmacologically acceptable derivative, is substantially nontoxic to warm-blooded animals, and is converted into the compound of the present invention in vivo. If possible, they are all the intention of the present invention.

Next, a typical method for producing Compound I will be described. Compound I has the formula II:

Embedded image (Wherein R ¹ , R ² and R ³ are as defined above, and R ¹¹ is —OCH ₃ , —OCH ₂ COOH or —OC
A compound represented by H ₂ —R ⁴ —R ⁵ —R ⁶ —R ⁸ (wherein R ⁴ , R ⁵ and R ⁶ are as defined above, and R ⁸ is —COOH or —SO ₂ NH ₂ ) or The reactive derivative and the following formula:

Embedded image 2- (2-guanidino) -1,3-thiazol-4-ylmethylthio) ethylamine or 1-methoxy-3-((2-guanidino-1,3-thiazol-4-yl) methylthio) propylimino represented by

Embedded image Can be obtained by appropriately coupling a 3- (3- (piperidinomethyl) phenoxynopropylamine or a reactive derivative thereof represented by the formula (I) with a known acid-base reaction. The intermediate compound II also has a selective antagonism at the gastrin receptor.

Gastrin is cholecystokinin (CCK)
Together, they belong to the so-called gastrin group gastrointestinal peptide hormones. The gastrin receptor is also present in the entire upper gastrointestinal tract, pancreas, liver, biliary tract, etc., but is mainly present in fundic gland wall cells, and regulates gastric acid secretion. On the other hand, CCK receptors are present in the periphery such as the digestive tract (called CCK-A receptors) and centrally located in the brain (CCCK-A receptors).
Known as KB receptors) and are involved in the regulation of gastrointestinal motility, pancreatic juice secretion and central action, appetite and the like. Thus, antagonists to these receptors have been used to treat the respective peptide hormone-related diseases in the gastrointestinal and central nervous systems of various animals, including humans,
For example, antineoplastic drugs or drugs for treating pancreatitis, gallbladder, reducing gallstone attacks, improving appetite, irritable bowel syndrome
Syndrome) is considered to be useful. Studies on receptors in the gastrointestinal and central tracts have also revealed the importance of these hormones as bioactive substances ("Brain and peptide" metabolism, Vol. 18, No. 10, 33
-44 (1981) and JP-A-63-238069).

[0011] These hormones are closely related chemically. That is, gastrin and the CCK peptide are C-terminal 5
Amino acid residues are common, gastrin receptor and CCK
High homology is observed between the receptor, particularly the CCK-B receptor. Therefore, gastrin receptor antagonists and C
Cross-reaction with CK-B receptor antagonists has been a problem. For example, gastrointestinal ulcer, Zollinger-Ellison syndrome,
Gastrin receptor antagonists are thought to be useful for the treatment of sinus C cell hyperplasia and gastrin-related diseases such as decreased gastrin activity. However, there is a risk of central side effects due to cross-reaction with CCK-B receptor. However, it was difficult to sufficiently achieve the purpose of treatment. Of course, for the treatment of gastrin-related diseases, it is desirable to use substances that specifically antagonize gastrin receptors to avoid central side effects. For example, the utility of gastrin receptor-specific antagonists in the treatment of gastric ulcers has been pointed out (metabolic 29 /
7, 1992). An anti-gastric ulcer having gastrin receptor antagonism has already been reported (Japanese Unexamined Patent Publication No. 63-2 / 1988).
No. 38069), as described above, a substance that selectively acts only on a gastrin receptor due to high homology with a CCK receptor has not yet been known.

Therefore, Compound II is also useful as a therapeutic agent for gastrin-related diseases such as gastric ulcer without central side effects. Compound II is described in, for example, JP-A-63-2
According to the method described in JP-A-38069, it can be synthesized from a known compound represented by the following formula using a known method as appropriate.

Embedded image In the formula II, a compound II in which R ¹ is hydrogen, R ² is methyl, R ³ is methyl (particularly m-position), and R ¹¹ is —OCH ₂ COOCH ₃ is particularly preferable. The compound I or the compound II is appropriately converted into a pharmaceutically acceptable salt by a known method. Examples of the acid addition salt include hydrochloric acid, hydrobromic acid,
Inorganic acid salts such as sulfuric acid, sulfamic acid, and phosphoric acid, and organic acid salts such as nitric acid or acetic acid, citric acid, lactic acid, methanesulfonic acid, propionic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, oxalic acid, and benzoic acid Is exemplified.

The usefulness of the benzodiazepine derivative of the present invention as an antiulcer agent will be described. We have found that H ₂
Various studies were conducted to develop a method for preventing ulcer recurrence after healing. As a result, a new finding that gastrin receptor antagonism can prevent (1) acid rebound phenomenon and (2) deterioration of gastric mucosal protective function, which causes recurrence of ulcer, has been reported as a representative H ₂ B famotidine. And a gastrin receptor antagonist (see Experimental Example 3).
This finding, of course, suggests that gastrin receptor antagonism is effective in preventing ulcer recurrence after H ₂ B healing.

Next, the present inventors examined the histamine H ₂ receptor antagonism and gastrin receptor antagonism of various compounds, and found that the benzodiazepine derivative of the present invention had these two kinds of effects. (See Experimental Examples 1 and 2 described later). The above results indicate that the benzodiazepine derivative of the present invention has a low ulcer recurrence rate of H _2.
This indicates that B is useful. When the benzodiazepine derivative of the present invention is used for treating ulcer, the derivative can be administered orally or parenterally. When administered orally, the compound of the present invention can be prepared by any of the usual preparations, for example, solid preparations such as tablets, powders, granules and capsules; solutions; oily suspensions; and liquid preparations such as syrups and elixirs. It can also be used as a dosage form. When administered parenterally, the compounds of the present invention can be used as aqueous or oily suspension injections. Upon its preparation, any of conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, etc. can be used, and other additives such as preservatives, stable It may contain an agent or the like. The dose of the compound of the present invention varies depending on the method of administration, the age, weight, condition and type of disease of the patient, but is usually about 20 to 300 per adult per day.
mg, preferably about 50 to 100 mg, may be administered in 1 to 5 divided doses. Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. In the following examples, as a group of part of the R ⁷ of the following compound (I), indicated by abbreviations.

FAA:

Embedded image FAB:

Embedded image TZA

Embedded image TZB

Embedded image

Reference Example 1 Preparation of compound IV-9

Embedded image 1) Ethyl m-formylphenoxyacetate (IV-1) A solution of m-hydroxybenzaldehyde (32.87 g, 0.296 mol) in tetrahydrofuran (100 ml) and dimethylformamide (100 ml) at 0 ° C under a nitrogen atmosphere at 60% Sodium hydride was added.
The mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (259 g) (hexane: ethyl acetate; 10: 1-4: 1) to give 51.76 g of acetate.
(92.3%). The eluate was used for the next step without further purification.

2) Ethyl 3- (2- (N-methyl) amino) phenylhydroxymethyl) phenoxyacetate (IV
-2) In a nitrogen atmosphere, add 1M boron trichloride solution (180ml)
While cooling with ice, N-methylaniline (15.9 g, 0.14 g) was added.
A solution of 8 mol) in benzene (90 ml) was added dropwise. The mixture was heated at reflux for 3 hours (hydrogen chloride gas evolved). The solution was cooled to 0 ° C., and the aldehyde (IV-
1: 30 g, 0.144 mol) and triethylamine (35
g, 0.346 mol) in benzene (90 ml). The mixture was stirred at room temperature for 1 hour. Ice-cooled diluted hydrochloric acid was added. The aqueous layer was separated, and the organic layer was extracted with diluted hydrochloric acid.
The aqueous layers were combined, made basic with 10% sodium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ether and 35.13 g of the alcohol (IV-2) (77.3)
%). mp = 94-95 ° C

3) 2- (N- (chloroacetyl) -N-
Methylamino) -3 ′-(carbethoxymethoxy) benzophenone (IV-3) Chloroacetyl chloride (7.
A solution of 56 g (66.9 mmol) in dichloromethane (20 ml) was added to an amino alcohol (IV-2; 20.85 g, 6).
6.11 mmol) and pyridine (5.30 g) in dichloromethane (70 ml) were added dropwise and the mixture was stirred at 0 ° C. for 1 hour. Ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual acetone (20
(0 ml) to the solution at 0 ° C., the Jone's reagent was added dropwise. The mixture was stirred for 1 hour and water was added. The mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was crystallized from ether to obtain 24.17 g (93.8%) of a ketone compound (IV-3). mp
= 130-131 ° C

4) 1-methyl-5- (3- (carbethoxymethyloxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-4) Benzophenone (IV-3; 23.0) obtained in the above 3).
g, 59.0 mmol), sodium iodide (9.0 g, 6
0.0 mmol), and ammonium carbonate (60 g, 0.1 g).
(624 mmol) in acetonitrile (650 ml) was stirred at room temperature for 3 days. Insoluble materials were distilled off under reduced pressure.
The residue was dissolved in ethyl acetate, the solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (220 g) (hexane: ethyl acetate; 1: 1) to give benzophenone 2
0.35 g (97.9%) was obtained.

5) 1-methyl-5- (3- (carboxymethoxy) phenyl) -1,3-dihydro-2H-1,
4-benzodiazepin-2-one (IV-5) Ester (IV-4; 33.95 g, 9) obtained in 4) above.
6.3 mmol) in methanol (100 ml)
100 ml of aqueous sodium hydroxide solution were added. The solution was left at room temperature for 20 hours. Water was added and the mixture was washed with ether, acidified with 10% hydrochloric acid and extracted continuously with chloroform for 30 hours. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 31.5 g of crude carboxylic acid (99.5).
%). The product was used for the next step without further purification.

6) 1-methyl-3-methoxyimino-5
-(3- (carbomethoxymethoxy) phenyl) -1,
3-dihydro-2H-1,4-benzodiazepine-2-
On (IV-6) The crude carboxylic acid obtained in 5) above (IV-5; 22.5 g,
To a solution of 80.2 mmol) in dimethylformamide (400 ml) was added potassium t-butoxide (22.5 g, 0.201 mol) at -20 ° C under a nitrogen atmosphere. The mixture was stirred at −20 ° C. for 20 minutes, and a solution of isoamylnitrile (9.8 g, 83.7 mmol) in dimethylformamide (30 ml) was added at −20 ° C., and the mixture was stirred for 1 hour. A solution of dimethyl sulfate (20 ml, 0.211 mol) in dimethylformamide (30 ml) was added at -20 ° C. The mixture is -2
The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 15 hours. Ethyl acetate was added and the solution was washed with water, 5% sodium carbonate, 5% hydrochloric acid solution, and water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was flash chromatographed on silica gel (250 g) (ethyl acetate: hexane; 1:
1 and 3: 2) to give a 4: 1 mixture of the methoxime (20 g) isomers. Recrystallization from methanol: ether gave 10.1 g (32.9%) of the major isomer as crystals. mp = 97-99 ° C. The mother liquor was purified by flash chromatography on silica gel (130 g) (ethyl acetate: hexane (1: 1 → 3: 2) and 7.41 g (2.
4.2%, yield 57.1%).

7) 1-methyl-3-amino-5- (3-
(Carbomethoxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-7) Methoxme obtained in 6) above (IV-6; 20.8 g, 5
A solution of 4.6 mmol) and 5% ruthenium-carbon (5.3 g) in methanol (150 ml) was hydrogenated with hydrogen (17 kg / cm ² ) at 65 ° C. for 20 hours. Final pressure 9kg /
cm ² . The catalyst was filtered, and the filtrate was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate and extracted with 5% aqueous hydrochloric acid. The extract was washed with ethyl acetate and made basic with aqueous sodium carbonate. The mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used for the next step without purification.

8) 1-methyl-3- (N '-(m-tolyl) ureido) 5- (3-carbomethoxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2- ON (IV-8) The crude amine obtained in 7) above (IV-7; 13.5 g, 38.
2 mmol), a mixture of triethylamine (7 ml) and m-tolyl isocyanate (4.96 g, 37.3 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 20 hours. Ethyl acetate was added, and the mixture was washed with water, 50% aqueous hydrochloric acid, and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 10.8 g of the target substance. The mother liquor was subjected to flash chromatography on silica gel (100 g) (ethyl acetate: hexane; 1: 1 and ethyl acetate),
Crystallization from ether gave 2.65 g of the desired compound (yield 7).
4.2%). mp = 227-231 ° C

9) 1-methyl-3- (N '-(m-tolyl) ureido) 5- (3-carboxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-9) The ether obtained in the above 8) (IV-8; 11.78 g, 2
(4.2 mmol) in methanol and 0.5 N sodium hydroxide (120 ml) were warmed at 60 ° C. for 30 minutes and the solution was left at room temperature for 2 hours. Water was added, the solution was washed with chloroform, concentrated to 500 ml, acidified with dilute hydrochloric acid and extracted with chloroform-methanol (4: 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ether to give 10.89 g of the desired carboxylic acid
(95.2%). mp = 154-157 ° C. IRνmax (KBr): 3370, 1734, 164
4,1600,1552 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.31 (3H,
s), 3.49 (3H, s), 4.65 (2H, s),
5.54 (1H, s), 6.83 (1H, m), 7.0
5-7.45 (10H, m), 7.64 (1H, m) Elemental analysis _{(C 26 H 24 N 4 O} 5 0.7H 2 O as) Found: C, 64.36; H, 5 . 48; N, 11.8
0 Calculated: C, 64.37; H, 5.28; N, 11.5
5

Reference Example 2 1-methyl-3- (N '-(m-tolyl) ureido)-
5- (3-anisyl) -1,3-dihydro-2H-1,
Production of 4-benzodiazepin-2-one (IV-96)

Embedded image

Embedded image 1) 2-N-methylanilino-3-anisylcarbinol (IV-191) According to the production method of compound (IV-2) described in Reference Example 1, m
-Synthesized from anisaldehyde. Yield 84.7%. mp = 84 ° C. IRνmax (nujol): 3320, 3150, 161
3,1606,1583,1500 cm ^-1 . NMR (CDCl ₃ ) δ: 2.78 (3H, s), 3.
79 (3H, s), 5.81 (1H, s), 6.68
(2H, m), 6.84 (1H, m), 6.96 (3
H, m), 7.25 (2H , m) Elemental analysis (C ₁₅ as H ₁₇ NO ₂₎ Found: C, 73.97; H, 7.14 ; N, 5.92 Calculated: C, 74 H, 7.04; N, 5.76 2) 2- (N-methyl-N-chloroacetylamino)-
3′-Methoxybenzophenone (IV-92) Compound IV-191 in the same manner as in the production of compound IV-3.
Was converted to IV-192. Yield 54.9%. NMR (CDCl ₃ ) δ: 3.09 (3H, s), 3.
86 (3H, s), 3.92 (2H, m), 7.01-
7.7 (8H, m) 3) 1-methyl-5- (m-anisyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-193) Compound IV-192 in the same manner as in the production of compound IV-4
Was converted to IV-193. Yield 87.0%. NMR (CDCl ₃ ) δ: 3.41 (3H, s), 3.
78 (1H, d, J = 10.8 Hz), 3.84 (3
H, s), 4.81 (1H, d, J = 10.8 Hz),
6.95-7.4 (7H, m), 7.55 (1H, m) 4) 1-methyl-3- (hydroxyimino) -5- (3
-Anisyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-194) Compound IV-193 in the same manner as in the production of compound IV-6.
Was converted to compound 1V-194. Yield 91.8%. NMR (CDCl ₃ ) δ: 3.47 (3H, s), 3.
85 (3H, s), 7.05-7.5 (7H, m),
7.57 (1H, m) 5) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3-anisyl) -1,3-dihydro-2H
-1,4-benzodiazepin-2-one (IV-19
6) Compound IV-194 in the same manner as in the production of compound IV-7
Was converted to IV-196. Yield 69.6% (from oxime). mp = 216-217 ° C. IRνmax (nujol): 3300, 1677, 164
2,1565 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 3.48 (3H, s), 3.83 (3H, s),
6.85 (1H, m), 7.0-7.5 (10H,
m), 7.61 (1H, m ) Elemental analysis (C ₂₅ as H ₂₄ N ₄ O ₃₎ Found: C, 68.95; H, 5.67 ; N, 12.6
9

Reference Example 3

Embedded image 1) 2- (3- (3-piperidinomethyl) phenoxy)
Propylcarbamoyl) ethylamine (III-34)
Preparation of N-butoxycarbonyl-β-alanine (1.89
g), a mixture of 3- (3- (piperidinomethyl) phenoxy) propylamine (2.32 g), dicyclohexylcarbodiimide (2.06 g) and 1-hydroxybenzotriazole (0.135 g) in tetrahydrofuran is stirred at room temperature for 3 hours. . The resulting crystals are filtered and washed with tetrahydrofuran. The residue obtained by concentrating the filtrate under reduced pressure is dissolved in ethyl acetate. The insolubles are filtered off and the filtrate is concentrated. The residue was chromatographed [A: 150 g of silica gel, methylene chloride / methanol (9: 1 → 4:
1); then B: 150 g of silica gel, ethyl acetate / methanol (9: 1)]. NMR (CDCl ₃ ) δ: 1.42 (9H, s);
44 (2H, m), 1.59 (4H, m), 1.99
(2H, m), 2.40 (4H, m), 3.42 (4
H, m), 4.05 (2H, t, J = 6.0 Hz),
6.78 (1H, m), 6.92 (2H, s), 7.2
1 (1H, m) IR max (film): 3320, 1692, 16
46, 1527, 1169 cm ^-1

2) Production of Compound (III-31, 32, 33, 35) According to the reaction of 1), the compound is synthesized by coupling the corresponding N-BOC amino acid and then deprotecting. The physical constants of the protected form of each compound are shown below. a) N-BOC- (2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoylmethylamine IRνmax (CHCl ₃ ): 3430, 1675, 16
20,1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD)
δ: 1.46 (9H, s), 2.68 (2H, t, J =
7 Hz), 3.41 (2H, t, J = 7 Hz), 3.6
6 (2H, s), 3.73 (2H, s), 6.47 (1
H, s) Elemental analysis _{(C 14 H 24 N 6 S} 2 O 3 H 2 O as) Found: C, 41.73; H, 6.18 : N, 20.7
9; S, 15.72 Calculated: C, 41.36; H, 6.45; N, 20.6
7; S, 15.77b) N-BOC-2- (2- (2-
Guanidino-1,3-thiazolyl-4-ylmethylthio) ethylcarbamoyl) ethylamine mp = 124-125 ° C. IRνmax (KBr): 3380, 3115, 170
0,1658, 1608, 1550, 1514 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.44 (9H,
s), 1.76 (2H, qui, J = 7 Hz), 2.1
7 (2H, t, J = 7 Hz), 2.69 (2H, t, J
= 7Hz), 3.10 (2H, t, J = 7Hz), 3.
36 (2H, t, J = 6 Hz), 3.65 (2H, t, J = 6 Hz)
s), 6.45 (1H, s ) Elemental analysis _{(C 16 H 28 N 6 O} 3 as S) Found: C, 46.02; H, 6.65 ; N, 19.9
7; S, 15.40 Calculated: C, 46.13; H, 6.78; N, 20.1
7; S, 15.40 c) N-BOC-3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethylamine IRvmax (film): 3300, 1705, 16
62, 1528 cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (9H, s);
45 (2H, m), 1.57 (4H, m), 2.00
(2H, m), 2.40 (4H, m), 3.46 (2
H, s), 3.51 (2H, t, J = 7 Hz), 3.7
7 (2H, d, J = 6 Hz), 4.08 (2H, t, J
= 6 Hz), 6.75-7.0 (2H), 7.15-
7.25 (2H) Elemental analysis (C ₂₂ H ₃₅ N ₃ as O ₄₎ Found: C, 64.87; H, 8.71 ; N, 10.0
6 Calculated: C, 65.16; H, 8.70; N, 10.3
6

D) N-BOC-3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propylamine IRνmax (CHCl ₃ ): 3465,3325,1
702, 1664, 1603, 1588, 1490 cm
^-1 NMR (CDCl ₃ ) δ: 1.438 (9H, s),
1.59 (4H, m), 1.81 (2H, qui. J =
7 Hz), 2.01 (2H, qui. J = 6 Hz),
2.22 (2H, t, J = 7 Hz), 2.40 (4H,
m), 3.17 (2H, q, J = 7 Hz), 3.41-
3.53 (4H), 4.80 (1H, m), 6.42
(1H, br.s), 6.78 (1H, m), 6.86
−6.97 (2H), 7.22 (1H, t, J = 8H)
z)

Example 1 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (2-guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoylmethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1, 4-benzodiazepin-2-one (IV-21), 1-methyl-3-
(N '-(m-tolyl) ureido) -5- (3- (2-
(2- (2-guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoylethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-22) and 1-methyl-3- (N ′-(m-tolyl) ureido) -5- (3- (3- (3- (2-guanidino-1) ,
3-thiazol-4-yl) methylthio) ethylcarbamoylpropylcarbamoylmethoxy) phenyl)-
1,3-dihydro-2H-1,4-benzodiazepine-
Production of 2-one (IV-23)

Embedded image The coupling between carboxylic acid (IV-9) and amine (III-30) was performed by the following method. Carboxylic acid (IV
-9) (236 mg, 0.499 mmol), 3- (2- (2
-Guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) methylamine dihydrochloride (2
17 mg, 0.601 mmol), N, N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (140
mg, 0.730 mmol) and 1-hydroxybenzotriazole monohydrate (30 mg, 0.197 mmol) in dimethylformamide (7 ml) and triethylamine (0.
(25 ml) is stirred overnight at room temperature and concentrated to 1 mmHg. Water is added and the solid is collected by filtration, washed with water, dried and subjected to flash chromatography (silica gel, 50 g; chloroform / methanol (9: 1)) in chloroform / methanol (9: 1). The eluate is solidified in methanol / chloroform and dried to give the coupling product IV-21 (200 mg, 53.9%). In the same manner as described above, the carboxylic acid (IV-9) and the amine (III-31), and the carboxylic acid (IV-9) and the amine (III-32) are coupled to give the corresponding product (IV-22). And (IV-23) in a yield of 8
Obtained at 7.0% and 57.7%.

Compound IV-21 mp = 145-147 ° C. IR νmax (KBr): 3360, 1656, 161
0.1541 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.65 (2H, t, J = 7 Hz), 3.38
(2H, t, J = 7 Hz), 3.49 (3H, s),
3.62 (2H, s), 3.94 (2H, s), 4.5
7 (2H, s), 5.48 (1H, s), 6.45 (1
H, s), 6.83 (1H, m), 7.05-7.46.
(10H, m), 7.63 ( 1H, m) Elemental analysis _{(C 38 H 38 N 10 O} 5 S 2 1.2H 2 O as) Found: C, 55.06; H, 5.36 ; N , 18.
20; S, 8.14 Calculated: C, 54.99; H, 5.33; N, 18;
32; S, 8.39 compound IV-22 mp = 141-143 ° C IRνmax (KBr): 3340, 1645, 161
2,1545 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.31 (3
H, s), 2.43 (2H, t, J = 6 Hz), 2.5
6 (2H, t, J = 7 Hz), 3.32 (2H, t, J
= 7 Hz), 3.49 (5H, s), 3.57 (2H,
t, J = 6 Hz), 4.50 (2H, s), 5.46
(1H, s), 6.42 (1H, s), 6.85 (1
H, m), 7.02-7.46 (14H, m), 7.6.
3 (1H, m) Elemental analysis _{(C 36 H 45 N 10 O} 5 S 2 H 2 O) Found: C, 55.72; H, 5.60 ; N, 18.
16; S, 8.04 Calculated: C, 55.80; H, 5.46; N, 18;
08; S, 8.28 Compound IV-23 IRνmax (KBr): 3360, 1645, 161
0,1543 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.84 (2H,
qui, J = 7 Hz), 2.18 (2H, t, J = 7H)
z), 2.30 (3H, s), 2.63 (2H, t, J
= 7 Hz), 2.33 (2H, t, J = 6 Hz), 3.
34 (2H, t, J = 6 Hz), 3.48 (3H,
s), 3.60 (2H, s), 4.51 (2H, s),
5.48 (1H, s), 6.44 (1H, s), 6.8
3 (1H, m), 7.07-7.47 (10H, m),
7.63 (1H, m) Elemental analysis _{(C 37 H 42 N 10 O} 5 S 2 O.3H 2 O as) Found: C, 57.37; H, 5.55 ; N, 17.
83; S, 8.10 Calculated: C, 57.24; H, 5.53; N, 18;
04; S, 8.26

Example 2 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-24), 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (3- (piperidinomethyl) phenoxy) propylcarbamoylethylcarbamoylmethoxy) phenyl) -1,3 -Dihydro-2H-
1,4-benzodiazepin-2-one (IV-25),
1-methyl-3- (N '-(m-tolyl) ureido)-
5- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylpropylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-26) and 1- Methyl-3- (N '-(m-tolyl) ureido) -5
(3- (5- (3- (piperidinomethyl) phenoxy)
Propylcarbamoylpentylcarbamoylmethoxy)
Production of (phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-27)

Embedded image

Triethylamine (0.4 ml) was added to carboxylic acid IV-9 (236 mg, 0.499 mmol), N, N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (145 mg), amine III-33 dihydrochloride ( 30
(0 mg, 0.756 mmol) and 1-hydroxypentztriazole monohydrate (30 mg) in a dimerlformamide (7 ml) mixture under ice cooling. The mixture is stirred overnight at room temperature and concentrated at 1 mm Hg, 40 ° C. Water is added and the solids are collected by filtration and chromatographed (silica gel, 2
Purification over 5 g; chloroform / methanol (5: 1) affords 186 mg (48.9%) of solid IV-24. Similarly to the above, acid IV-9 and amine III-3
4, III-35, III-36 and the corresponding compounds IV-25, IV-26 and IV
-27 in 60.9%, 60.9% and 62.2% yield
I got it.

Compound IV-24 amorphous powder IRνmax (KBr): 3320, 1670, 164
3,1610,1600,1565 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
62 (4H, m), 1.96 (2H, qui., J = 6
Hz), 2.27 (3H, s), 2.47 (4H,
m), 3.42 (3H, s), 3.46 (2H, q, J
= 6 Hz), 3.52 (2H, m), 4.00 (4H,
m), 4.49 (2H, s), 5.52 (1H, d, J
= 8 Hz), 6.72-6.92 (4H), 7.05-
7.40 (11H, m), 7.50-7.63 (2H,
m), 7.67 (1H, s ) Elemental analysis _{(C 43 H 49 N 7 O} 6 1.2H 2 O as) Found: C, 66.01; H, 6.66 ; N, 12.
75 calc: C, 66.09; H, 6.63; N, 12.
55

Compound IV-25 amorphous powder IRνmax (KBr): 3320, 1670, 164
2,1611,1600,1555 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
61 (4H, m), 1.87 (2H, m), 2.28
(3H, s), 2.45 (6H, m), 3.32 (2
H, q, J = 6 Hz), 3.43 (3H, s), 3.5
0 (2H, s), 3.63 (2H, q, J = 6 Hz),
3.95 (2H, t, J = 6 Hz), 4.46 (2H,
s), 5.52 (1H, d, J = 8 Hz), 6.56
(1H, t, J = 5 Hz), 6.72 (1H, m),
6.80-7.40 (16H, m), 7.55 (1H,
m), 7.60 (1H, s ) Elemental analysis _{(C 44 H 51 N 7 O} 6 H 2 O as) Found: C, 66.48; H, 6.77 ; N, 12.
60 calc: C, 66.73; H, 6.75; N, 12.
38

Compound IV-26 amorphous powder IRνmax (KBr): 3400, 3320, 167
1,1642,1610,1554 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
61 (4H, m), 1.75-2.05 (4H), 2.
22 (2H, t, J = 7 Hz), 2.28 (3H,
s), 2.55 (4H, m), 3.38 (4H, m),
3.44 (3H, s), 3.50 (2H, s), 3.9
9 (2H, t, J = 6 Hz), 4.48 (2H, s),
5.52 (1H, d, J = 8 Hz), 6.63 (1H,
m), 6.75 (1H, m), 6.79-7.42 (1
6H, m), 7.57 (1H, m), 7.70 (1H,
s) Elemental analysis _{(C 45 H 53 N 7 O} 6 H 2 O as) Found: C, 67.13; H, 6.69 ; N, 12.
30 Calculated: C, 67.06; H, 6.88; N, 12.
17

Compound IV-27 amorphous powder (from methanol-water) IR νmax (KBr): 3300, 1670, 164
0,1608,1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.72 (12
H), 1.91 (2H, qui. J = 6.0 Hz),
2.16 (2H, t, J = 7.2 Hz), 2.28 (3
H, s), 2.43 (4H, br.s), 3.31 (2
H, q, J = 6.6 Hz), 3.42 (2H, t, J =
6.0 Hz), 3.45 (3H, s), 3.49 (2
H, s), 4.01 (2H, t, J = 6.1 Hz),
4.49 (2H, s), 5.54 (1H, d, J = 7.
8Hz), 6.23 (1H, br.s), 6.62-
7.44 (17H, m), 7.63 (1H, s) Elemental analysis _{(C 47 H 57 O 6 N} 7 0.8H 2 O as) Found: C, 67.82; H, 7.04 ; N, 11.
93 Calculated: C, 67.98; H, 7.11; N, 11.
81

Example 3 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (3-
Production of (piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-28)

Embedded image (1) 4-azido-but-2-enoic acid (compound III-
47) 4-Bromo-but-2-enoic acid (825 mg, 5.0 mmol)
l) and sodium azide (1.0 g, 15.3 mmol)
Of HMPA (5 ml) is stirred at room temperature for 2 hours.
Ethyl acetate is added, the mixture is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. (2) 3- (3- (Piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylazide (Compound III-48) 3- (3- (Piperidinomethyl) phenoxy) propylamine (Compound III-28) (1.0 g) And the product of the above (1) (III-47) (0.60 g) were coupled in the same manner as in Example 1 to give compound III
-48 (1.063 g, 73.9%) is obtained. (3) 3- (3- (3- (Piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylamine (Compound III-49) Azide (III-48, 1.30 produced in the above (2))
g, 3.64 mM) and triphenylphosphine (1.
(G, 3.82 mM) in tetrahydrofuran (20 ml) is stirred at room temperature overnight. Water (3 ml) is added and the solution is heated at reflux for 30 minutes. Volatiles are removed in vacuo, the residue is dissolved in ethyl acetate and the solution is extracted with dilute hydrochloric acid. The extract is washed with ethyl acetate and extracted with chloroform. The solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 810 mg (70.1%) of a solid. (4) Carboxylic acid (IV-9) (473 mg, 1.001)
mmol) and amine (III-49) (360 mg, 1.08
6 mmol) in the same manner as in Example 2 to obtain 444 mg (56.5%) of compound (IV-28).

Compound IV-28 IRνmax (KBr): 3380, 3310, 167
0,1641,1610 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
63 (4H, m), 1.91 (2H, quint, J =
6.1 Hz), 2.24 (3H, s), 2.48 (4
H, br. s), 3.43 (5H, s), 3.53 (2
H, s), 3.88-4.12 (4H, m), 4.51.
(2H, s), 5.52 (1H, d, J = 7.8H)
z), 5.90 (1H, d, J = 15.6 Hz), 6.
65-7.46 (19H, m), 7.56 (1H,
m), 7.84 (1 H, s) Elemental analysis (as C ₄₅ H ₅₁ N ₇ O ₆ 1.5 H ₂ O) Found: C, 66.31; H, 6.61; N, 12.
23 Calculated: C, 66.48; H, 6.70; N, 12.
06

Example 4 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (3-
(Piperidinomethyl) phenoxy) propylcarbamoyl) -2-chloro-prop-3-enylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Production of benzodiazepin-2-one (IV-33)

Embedded image 1) N-Boc-propargylamine (IV-29) A solution of g-tert-butyl dicarbonate (7.0 g, 32 mM) in acetone (6 ml) was added to propargylamine (1.65).
3 g, 30 mM) acetone (8 ml) and water (1 m
l) The solution was added dropwise under ice cooling. The solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was chromatographed on silica gel (115 g), hexane: ethyl acetate (0-35%) to give 4.118 g of a colorless solid (88.4 yield).
%).

2) 4- (Boc-amino) but-2-ynoic acid (IV-30) 3M solution of ethylmagnesium bromide in ether (8
ml, 24 mM) with compound (IV-29) (1.552 g,
10 mM) in tetrahydrofuran (10 ml).
It was added dropwise at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The mixture was added at 0 ° C. for 5 minutes, at room temperature for 30 minutes,
Dry carbon dioxide gas was introduced. Water was added. The mixture was washed with ether, acidified with 10% citric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 1.682 g (84.
4%). This was used for the next step without purification. 3) N-Boc-3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propynylamine (IV-31) Coupling was performed in the same manner as described above, and the yield was 5
The desired compound was obtained at 6.0%.

4) 3- (3- (3- (Piperidinomethyl) phenoxy) propylcarbamoyl) -2-chloro-prop-enylamine (IV-32) Ethyl acetate of compound (IV-31) (719 mg, 1.67 mM) To a stirred solution of (8 ml) a solution of 4N HCl in ethyl acetate (4 ml) was added. The mixture was stirred at room temperature for 16 hours. The precipitated material is collected by decantation, and water (20m
l) dissolved. The solution was made basic with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 549 mg of an oily substance.
(89.6%).

5) Compound (IV-33) Coupling was carried out in the same manner as in Example 2 to obtain the title compound in a yield of 60.4%. IRνmax (KBr): 3380, 1676, 161
0,1554 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m);
62 (4H, m), 1.93 (2H, quint, J =
6.2 Hz), 2.26 (3H, s), 2.45 (4
H, br. s), 3.26-3.60 (4H, m),
3.44 (3H, s), 3.98 (2H, t, J = 5.
7 Hz), 4.14 (2H, m), 4.56 (2H,
s), 5.48 (1H, d, J = 7.8 Hz), 6.2
0 (1H, s), 6.66-7.00 (7H, m),
7.04-7.43 (10H, m), 7.48-7.6
9 (2H, m), 7.82 (1H, br.s) elemental analysis _{(C 45 H 50 N 7 O} 6 Cl 0.3H as ₂ O) Found: C, 65.41; H, 6.23 N, 12.0
7; Cl, 4.51 Calculated: C, 65.45; H, 6.18; N, 11.8.
7; Cl, 4.29

Example 5 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (2- (2-
Guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoyl) propyl) -piperazinocarbomethoxy) phenyl-1,3-dihydro-2H-1,
4-benzodiazepin-2-one (IV-44) and its hydrochloride

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-carboethoxypropylpiperazino) carbomethoxy) phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-3
7) Carboxylic acid (IV-9) (945 mg, 2.000 mmol)
And N- (3-ethoxycarbonyl) propylpiperazine (401 mg, 2.001 mmol) were coupled in the same manner as in Example 2 to give compound (IV-37) in a yield of 65.6.
%. The residue was recrystallized from methanol-ether. mp = 179-182 [deg.] C. IR [nu] max (KBr): 3360, 1721, 167
8,1631,1608,1551 cm ^-1 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J =
7.2 Hz), 1.81 (2H, qui, J = 7.2H)
z), 2.30 (3H, s), 2.34 (2H, t, J
= 7.2 Hz), 2.41 (6H, m), 3.46 (3
H, s), 3.54 (2H, m), 3.62 (2H,
m), 4.14 (2H, q, J = 7.2 Hz), 4.7
0 (2H, s,), 5.55 (1H, d, J = 8.2H
z), 6.85 (1H, d, J = 6.6 Hz), 6.9
4 (1H, d, J = 8.2 Hz), 7.03-7.42
(11H, m), 7.59 ( 1H, m) Elemental analysis _{(C 36 H 42 O 6 N} 6 0.2H 2 O as) Found: C, 65.57; H, 6.62 ; N, 13 .
10 Calculated: C, 65.68; H, 6.49; N, 12.
77

2) Compound (IV-44) Ester (814 mg, 1.243 m) obtained in 1) above
M) was warmed and dissolved in methanol (22 ml). The solution was cooled to room temperature. 1 N sodium hydroxide (3 ml) was added. The solution was left at room temperature for 18 hours and concentrated under reduced pressure.
Dilute hydrochloric acid was added. The solution was left at room temperature for 18 hours and concentrated under reduced pressure. Dilute hydrochloric acid was added, the precipitate was collected by filtration, and benzene was added. Distill off volatiles to remove water,
After drying at 0.1 mmHg, 809 mg of hydrochloride (98.
2%). This was used in the next step without purification. Coupling was performed according to a conventional method, and the yield was 59.6%.
Afforded the title compound. IRνmax (KBr): 3335, 1640, 160
7,1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.77 (2H,
qui, J = 7.0 Hz), 2.20 (2H, t, J =
7.0 Hz), 2.30 (3H, s), 2.34 (2
H. t. J = 7.2 Hz), 2.42 (4H, m),
2.68 (2H, t, J = 6.4 Hz), 3.40 (2
H, t, J = 6.4 Hz), 3.49 (3H, s),
3.45-3.75 (4H, m), 3.62 ((2H,
s), 4.74 (2H, s), 5.50 (1H, s),
6.44 (1H, s), 6.82 (1H, m), 7.0
0-7.45 (10H, m), 7.62 (1H, m) Elemental analysis _{(hydrochloride, C 41 H 49 O 5 N} 11 S 2 3HCl 0.
5H ₂ O as) Found: C, 51.24; H, 5.62 ; Cl, 10.
N, 16.21; S, 6.53 Calculated: C, 51.38; H, 5.57; Cl, 11;
11; N, 16.08; S, 6.69

Example 6 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (3- (3-
(Piperidinomethyl) phenoxy) propylcarbamoyl) ethylpiperazinocarbomethoxy) phenyl)-
1,3-dihydro-2H-1,4-benzodiazepine-
2-one (IV-46)

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-carboethoxyethylpiperazino) carbomethoxy) phenyl) -1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-3
6) Carboxylic acid (IV-9) (634 mg, 1.342 mmol)
And N- (2-ethoxycarbonyl) ethylpiperazine (259 mg, 1.391 mmol) were coupled in the same manner as in Example 2 to give compound (IV-36) in a yield of 62.9%.
I got it. IRνmax (KBr): 3345, 1730, 166
0, 1608, 1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7)
Hz), 2.29 (3H, s), 2.35-2.57
(6H), 2.71 (2H, t, J = 7 Hz), 3.4
6 (3H, s), 3.54 (2H, m), 3.63 (2
H, m), 4.16 (2H, q, J = 7 Hz), 4.7
0 (2H, s), 5.56 (1H, d, J = 8 Hz),
6.85 (1H, d, J = 6 Hz), 6.99 (1H,
d, J = 8 Hz), 7.03-7.42 (11H,
m), 7.59 (1H, m ) Elemental analysis _{(C 35 H 40 N 6 O} 6 0.5H as ₂ O) Found: C, 64.93; H, 6.27 ; N, 12.8
1 Calculated: C, 64.70; H, 6.36; N, 12.9
3

2) Compound (IV-46) Coupling was carried out in the same manner as in Example 1 to obtain the title compound (IV-46) in a yield of 66.5%. Amorphous powder IRνmax (KBr): 3330, 1643, 159
9,1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m);
61 (4H, m), 1.99 (2H, qui, J = 6H
z), 2.28 (3H, s), 2.42 (10H,
m), 2.64 (2H, t, J = 6 Hz), 3.44
(5H, s), 3.50 (6H, m), 4.02 (2
H, t, J = 6 Hz), 4.64 (1H, d, J = 13)
Hz), 4.68 (1H, d, J = 13 Hz), 5.5
5 (1H, d, J = 8 Hz), 6.7-6.92 (3
H, m), 6.95-7.42 (13H, m), 7.4.
6-7.63 (3H) Elemental analysis _{(C 48 H 58 N 8 O} 6 0.9H as ₂ O) Found: C, 67.05; H, 7.01 ; N, 13.1
5 Calculated: C, 67.10; H, 7.02; N, 13.0.
4

3) Compound (IV-47) Yield: 60.7% IR max (KBr): 3325, 1665, 164
0, 1608, 1598, 1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (2H, m);
63 (4H, m), 1.82 (2H, m), 1.99
(2H, qui, J = 6.2 Hz), 2.20-2.5
5 (12H, m), 2.29 (3H, s), 3.33-
3.72 (8H, m), 3.44 (3H, s), 4.0
6 (2H, t, J = 5.9 Hz), 4.67 (1H,
d, J = 8.2 Hz), 6.34 (1H, br.s),
6.73-6.92 (3H, m), 6.98-7.42
(13H, m), 7.57 (1H, m), 7.74 (1
H, br. s) Elemental analysis _{(C 49 H 60 N 8 O} 6 H 2 as O) Found: C, 67.00; H, 7.08 ; N, 12.9
9 Calculated: C, 67.26; H, 7.14; N, 12.8.
1

Example 7 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (3- (3-
(Piperidinomethyl) phenoxy) carbamoylmethylthio) ethylcarbamoylmethoxy) phenyl-1,3
-Dihydro-2H-1,4-benzodiazepin-2-one (IV-50)

Embedded image From N-BOC-ethanethiol to Weda et al. [I. Ued
a, K .; Ishi, K .; Shinozaki, M .; Se
iki, H .; Arai and M.S. Hatanak
a, Chem. Pharm. Bull, 38 , 3035
(1990)] and IV-4 synthesized by a method similar to that described above.
Coupling was carried out in the same manner as in Example 2 to give the title compound (IV-50) in a yield of 85.2%. Amorphous powder (from methanol-water) IRνmax (KBr): 3310, 1670, 164
2,1610,1552 cm ^-1 NMR (CDCl ₃ ) δ: 1.43 (2H, m), 1.
98 (2H, qui, J = 6.1 Hz), 2.28 (3
H, s), 2.44 (4H, m), 2.73 (2H,
t, J = 6.7 Hz), 3.23 (2H, s), 3.4
5 (3H, s), 3.40-3.59 (6H), 4.0
3 (2H, t, J = 5.8 Hz), 4.46 (2H,
s), 5.54 (1H, d, J = 8.2 Hz), 6.7
5-6.91 (3H, m), 6.94-7.40 (15
H, m), 7.57 (1H, m), 7.64 (1H, b
r. s) Elemental analysis _{(C 45 H 53 N 7 O} 6 S 0.3H 2 O as) Found: C, 65.52; H, 6.50 ; N, 12.1
1; S, 3.63 Calculated: C, 65.48; H, 6.55; N, 11.8
8; S, 3.88

Example 8 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (1-amino-3- (2-guanidinone-1,3-thiazol-4-yl) methylthio) propyliminosulfonyl) propyl) carbamoyl) methoxy) phenyl)- 1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-55) and its 3R-isomer (IV-56)
And the 3S-isomer (IV-57)

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-sulfamoylpropylcarbamoylmethoxy) phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-52) 3-aminopropanesulfonamide (IV-51) and compound (IV-9) are coupled according to a conventional method.
Compound (IV-52) was obtained with a yield of 88.8%. Similarly, 3-aminopropanesulfonamide and compound (IV
-9) 3R-form (IV-16) or 3S-form (IV-)
18) to give the corresponding compound (IV-52) 3
The R-form (IV-53) or the 3S-form (IV-54) were obtained in yields of 89.3% and 81.0%, respectively.

Compound IV-52 mp = 145-147 ° C. IR νmax (KBr): 3325, 1647, 161
0.1550 cm ^-1 NMR (DMSO) δ: 1.84 (2H, m), 2.2
4 (3H, s), 2.94 (2H, m), 3.24 (2
H, m), 3.41 (3H, s), 4.49 (2H,
s), 5.24 (1H, d, J = 8.4 Hz), 6.7
−6.82 (3H, m), 7.05-7.26 (6H,
m), 7.31-7.55 (4H, m), 7.63-
7.81 (2H), 8.27 (1H, m), 8.99
(1H, s) Elemental analysis _{(C 29 H 32 O 6 N} 6 S 1.5H as ₂ O) Found: C, 56.22; H, 5.55 ; N, 13.7
2; S, 4.81 Calculated: C, 56.21; H, 5.69; N, 13.5.
6; S, 5.17

Compound IV-53 (3R-isomer) [α] _D +45.7 (24 ° C., c 0.945, DM
F) Elemental analysis _{(C 29 H 32 N 6 O} 6 S O.5H as ₂ O) Found: C, 57.95; H, 5.66 ; N, 13.
83; S, 5.22 Calculated: C, 57.89; H, 5.53; N, 13.
97; S, 5.33 Compound IV-54 (3S-isomer) [α] _D -48.3 (24 ° C., c 1.003, D
MF) Elemental analysis _{(C 29 H 32 N 6 O} 6 S 0.5H as ₂ O) Found: C, 57.84; H, 5.67 ; N, 13.
82; S, 5.21 Calculated: C, 57.89; H, 5.53; N, 13.
97; S, 5.33

2) Compounds IV-55, IV-56 and IV-57 imidate (III-106, 350 mg, 1.28 m
A solution of M) in methanol (6.5 ml) was added to a solution of sulfonamide (IV-52, 375 mg, 0.633 mM) in dimethylformamide (5 ml). The solution was left at room temperature for 15 days. Water was added, the solid was collected by filtration and subjected to flash chromatography using silica gel and chloroform: methanol (9: 1). The solid was dissolved in methanol and water was added. The solid was collected by filtration and dried to obtain 239 mg (45.3%) of a powder.
26 mg (33.6%) were recovered. IRνmax (KBr): 3375, 1650, 161
0,1548, 1323, 1163, 1112 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.06 (2H,
qui, J = 7.0 Hz), 2.30 (3H, s),
2.47 (2H, t, J = 7.3 Hz), 2.79 (2
H, t, J = 7.3 Hz), 3.02 (2H, t, J =
7.2 Hz), 3.46 (2H, t, J = 6.6H)
z), 3.49 (3H, s), 3.59 (2H, s),
4.53 (2H, s), 5.46 (1H, s), 6.4
8 (1H, s), 6.83 (1H, d, J = 6.2H)
z), 7.01-7.46 (10H, m), 7.64
(1H, m) Elemental analysis (C ₃₇ as _{H 43 N 11 O 6 S 3} ) Found: C, 53.06; H, 5.30 ; N, 18.3
6; S, 11.28 Calculated: C, 53.28, H, 5.20; N, 18.4
9; S, 11.53 Similarly, imidate (III-108) and sulfonamide (IV-54) were coupled in methanol for 7 days to give the 3S-isomer (IV-57) in a yield of 65.1.
%. The 3R-isomer (IV-56) was obtained by the reaction with the sulfonamide (IV-53).

Compound IV-57 (3S-isomer ) [α] _D -19.2 (24 ° C., c 1.032, DM
F) Elemental analysis _{(C 37 H 43 N 11 O} 6 S 3 H 2 as O) Found: C, 52.24; H, 5.54 ; N, 18.
16; S, 11.17 Calculated: C, 52.16; H, 5.32;
08; S, 11.29 Compound IV-56 (3R isomer) [α] _D +31.9 (24 ° C., c 1.154, DM
F) Elemental analysis _{(C 37 H 43 N 11 O} 6 S 3 0.5H 2 as O) Found: C, 52.75; H, 5.33 ; N, 18.
45; S, 11.66 Calculated: C, 52.71; H, 5.26; N, 18;
28; S, 11.41

Example 9 1-methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (1-amino-3- (2-guanidinone-1,3-thiazol-4-yl) methylthio) propyliminosulfonylamino) propylcarbamoyl) methoxy) phenyl)- 1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-60)

Embedded image 1) 3-aminopropaneaminosulfonamide (IV-
58) Bromide (III-113, HMPA in 30 ml)
1.80 g, 8.29 mM) and sodium azide (1.2 g, 18.46 mM) were stirred at 50 ° C. for 2 hours, poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. IRvmax (film): To a solution of the residue of 2092 cm ^-1 in tetrahydrofuran (30 ml) was added triphenylphosphine (2.18 g, 8.31 mM).
The solution was stirred at room temperature for 18 hours. Add water (6 ml)
The solution was heated at reflux for 30 minutes and concentrated under reduced pressure. Add water,
Insoluble substances were removed by filtration, and the filtrate was washed with ethyl acetate. The solution was concentrated under reduced pressure and 750 mg of amine (59.1).
%). This was used for the next step without purification.

2) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-aminosulfonylaminopropyl) carbamoylmethoxy) phenyl-1,
3-dihydro-2H-1,4-benzodiazepine-2-
On (IV-59) In the same manner as in Example 8 (1), the amine (IV-58) was reacted with the compound (IV-9) to give the sulfonamide (I
V-59) was obtained in a yield of 95.6%. mp = 136-138 ° C. IRνmax (KBr): 3315,1646,161
1,155,1320,1153 cm ^-1 NMR (DMSO) δ: 1.61 (2H, qui, J =
6.6 Hz), 2.24 (3H, s), 2.85 (2
H, q, J = 6.6 Hz), 3.16 (2H, q, J =
6.4 Hz), 3.41 (3H, s), 4.47 (2
H, s), 5.24 (1H, d, J = 8.4 Hz),
6.45 (1H, t, J = 6.4 Hz), 6.47 (2
H, s), 6.74 (1H, d, J = 6.4 Hz),
7.06-7.25 (6H, m), 7.31-7.53
(4H, m), 7.63-7.80 (2H), 8.13
(1H, t, J = 5.8Hz ), 8.98 (1H, s) Elemental analysis _{(C 29 H 33 N 7 O} 6 as S) Found: C, 57.56; H, 5.68 ; N , 16.
26; S, 5.00 Calculated: C, 57.32; H, 5.43; N, 16;
13; S, 5.28

3) Compound (IV-60) Sulfonamide (IV-59) and compound (III-108) were coupled in the same manner as in Example 8 to give compound (III-60) in a yield of 29.9. %. IRνmax (KBr): 3360, 1650, 160
8,1545,1322,1122 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.73 (2H,
qui, J = 6.3 Hz), 2.30 (3H, s),
2.43 (2H, t, J = 7.2 Hz), 2.7982
H, t, J = 7.2 Hz), 2.99 (2H, t, J =
6.3 Hz), 3.42 (2H, t, J = 6.3H)
z), 3.48 (3H, s), 3.55 (2H, s),
4.52 (2H, s), 5.46 (1H, s), 6.3
8 (1H, s), 6.83 (1H, m), 6.97-
7.46 (10H, m), 7.63 (1H, m) Elemental analysis (C ₃₇ H ₄₂ as N ₁₂ O ₆ S ₃₎ Found: C, 52.12; H, 5.26 ; N, 19 .7
4; S, 11.17 Calculated: C, 52.34; H, 5.22; N, 19.8
0; S, 11.33

Example 10 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (NB)
oc-N- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethyl) amino) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-6
1) and 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (N- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethyl) amino) ethyl Carbamoylmethoxy) phenyl)
-1,3-Dihydro-2H-1,4-benzodiazepin-2-one (IV-62)

Embedded image

The amine (III-135) and the acid (IV-
9) was coupled in the same manner as in Example 2 to obtain the title compound (IV-61) in a yield of 42.4%. IRνmax (KBr): 3350, 1665, 161
0,1601 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.37 (11
H, br. s), 1.98 (2H, m), 2.30 (3
H, s), 2.44 (4H, br.s), 3.48 (1
1H, br. s), 3.78 (2H, s), 4.01
(2H, m), 4.47 (2H, br.s), 5.50
(1H, s), 6.74-6.96 (4H, m), 7.
05-7.46 (11H, m), 7.62 (1H, m) Elemental analysis _{(C 50 H 62 N 8 O} 8 0.8H 2 O as) Found: C, 65.46; H, 7 . 02; N, 12.5
6 Calculated: C, 65.45; H, 6.99; N, 12.2
1

Compound (IV-61) (280 mg, 0.
To a solution of (31 mM) in ethyl acetate (6 ml) was added N-hydrogen chloride in ethyl acetate (2 ml) under ice cooling. The suspension was stirred at room temperature for 20 hours. The solid (272 mg) was collected by filtration. IRνmax (KBr): 3360, 1670, 159
8 cm ^-1 NMR (CD ₃ OD) δ: 1.35-2.00 (6H,
m), 2.01 (2H, m), 2.29 (3H, s),
2.95 (2H, m), 3.15-3.50 (6H,
m), 3.50-3.72 (2H, m), 3.58 (3
H, s), 3.87 (2H, s), 4.08 (2H,
t, J = 6 Hz), 4.25 (2H, s), 4.64
(2H, s), 5.56 (1H, s), 6.85 (1
H, d, J = 7 Hz), 6.99-7.57 (13H,
m), 7.74 (1H, d, J = 8 Hz), 7.90
(IH, m) Elemental analysis _{(C 45 H 54 N 8 O} 6 2.5HCl 0.3H 2 O as) Found: C, 60.27; H, 6.45 ; Cl, 9.7
1; N, 12.44 Calculated: C, 60.09; H, 6.40; Cl, 9.8
5; N, 12.46

Example 11 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (3,6-dioxa-7- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) heptylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H -1,4-
Benzodiazepin-2-one (IV-66) and its hydrochloride salt, and 1-methyl-3- (N ′-(m-tolyl) ureido) -5- (3- (2- (2- (3- (3 −
(Piperidinomethyl) phenoxy) propylcarbamoylmethoxy) ethoxy) ethoxy) carbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-67) and its hydrochloride

Embedded image

The amine (III-149) and the acid (IV-
9) was coupled in the same manner as in Example 2 to obtain the title compound (IV-66) or (IV-67) in yields of 69.0% and 66.2%, respectively. Compound IV-66 IRνmax (KBr): 3325,662,1608
cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m);
59 (4H, m), 2.02 (2H, qui, J = 6H
z), 2.29 (3H, s), 2.40 (4H, m),
3.43 (5H, s), 3.45-3.70 (10H,
m), 3.99 (2H, t, J = 6 Hz), 4.09
(2H, s), 4.49 (2H, s), 5.38 (1
H, d, J = 8 Hz), 6.69-7.42 (17H,
m), 7.47 (1H, m), 7.58 (1H, m),
7.85 (IH, br. S) Elemental analysis _{(C 47 H 57 N 7 O} 8 1.3H 2 O as) Found: C, 64.70; H, 6.75 ; N, 11.
44 calc: C, 64.78; H, 6.89; N, 11.
25 hydrochloride (as C ₄₇ H ₅₇ N ₇ O ₈ 1.1 HCl 0.5 H ₂ O) Found: C, 62.83; H, 6.71; Cl, 4.
27; N, 11.05 Calculated: C, 62.92; H, 6.64; Cl, 4.
35; N, 10.93

Compound IV-67 hydrochloride IRνmax (KBr): 3400, 3300, 306
0, 1668, 1639, 1608, 1552 cm ^-1 NMR (CD ₃ OD) δ: 1.35-1.90 (6H,
m), 1.98 (2H, quint, J = 6.6H)
z), 2.29 (3H, s), 2.91 (2H, m),
3.30-3.60 (8H, m), 3.51 (3H,
s), 3.57 (4H, s), 3.62 (4H, s),
3.94 (2H, s), 4.03 (2H, t, J = 6.
1 Hz), 4.19 (2H, s), 4.53 (2H,
s), 5.39 (1H, s), 6.82 (1H, m),
6.98-7.24 (8H, m), 7.29-7.43
(5H, m), 7.64 (1H, d, J = 8.0H)
z), 7.75 (1 H, m) Elemental analysis (as C ₄₉ H ₆₁ N ₇ O ₉ 1.2 HCl H ₂ O) Found: C, 61.69; H, 6.91; N, 10.
50; Cl, 4.36 Calculated: C, 61.70; H, 6.78;
28; Cl, 4.46

Example 12 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(2- (2- (2-guanidino-1,3-thiazole-
4-yl) methylthio) ethylcarbamoylmethoxy)
Ethoxy) ethoxycarbamoylmethoxy) phenyl)
-1,3-Dihydro-2H-1,4-benzodiazepin-2-one (IV-68)

Embedded image The amine (III-154) and the acid (IV-9) were coupled in the same manner as in Example 1 to give the title compound (IV-
68) was obtained with a yield of 69.5%. IRνmax (KBr): 3300, 1655, 160
5,1541 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.65 (2H, t, J = 6.8 Hz), 3.3
6-3.70 (16H, m), 3.48 (3H, s),
3.98 (2H, s), 4.52 (2H, s), 5.4
8 (1H, s), 6.45 (1H, s), 6.83 (1
H, m), 7.01-7.47 (10H, m), 7.6.
3 (1H, m) Elemental analysis _{(C 41 H 50 N 10 O} 8 S 2 2H 2 as O) Found: C, 53.93; H, 6.00 ; N, 15.4
S; 6.95 Calculated: C, 54.04; H, 5.97; N, 15.3
7; S, 7.04

Hydrochloride IRνmax (KBr): 3300, 1670, 163
8,1610,1550 cm ^-1 NMR (CD ₃ OD) DNA: 2.28 (3H,
s), 2.59 (2H, t, J = 7.0 Hz), 3.3
4-3.66 (14H, m), 3.49 (3H, s),
3.73 (2H, s), 3.94 (2H, s), 4.5
4 (2H, s), 5.36 (1H, s), 6.81 (1
H, m), 6.96 (1H, s), 7.05-7.23.
(5H, m), 7.27-7.40 (4H, m), 7.
61 (1H, d, J = 8.2 Hz), 7.71 (1H,
m) Elemental analysis _{(C 41 H 50 N 10 O} 8 S 2 HCl 0.5H as ₂ O) Found: C, 53.68; H, 5.77 ; N, 15.3
3: S, 6.75, Cl, 3.50 Calculated: C, 53.50; H, 5.69; N, 15.2
2; S, 6.97; Cl, 3.85

Example 13 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(3- (2- (2-guanidino-1,3-thiazole-
4-yl) methylthio) ethylcarbamoylpropyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-71) and its hydrochloride

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (2- (3- (carbomethoxy) propyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl)- 1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-69) The amine (III-163) and the acid (IV-9) were coupled in the same manner as described above to give the compound IV-69 in a yield of 6
Obtained at 7.4%. IRνmax (CHCl ₃ ): 3440, 1732, 1
678, 1602 cm ^-1 NMR (CDCl ₃ ) δ: 1.90 (2H, qui, J
= 7 Hz), 2.30 (3H, s), 2.40 (2H,
t, J = 7 Hz), 3.47 (3H, s), 3.48
(2H, t, J = 7 Hz), 3.50-3.62 (8
H, m), 3.67 (3H, s), 4.49 (2H,
s), 5.56 (1H, d, J = 8 Hz), 6.85
(1H, m), 6.92-7.43 (13H, m),
7.60 (1H, m). Elemental analysis _{(C 35 H 41 N 5 O} 8 0.7H 2 O as) Found: C, 62.43; H, 6.18 ; N, 10.
67 calc: C, 62.52; H, 6.36; N, 10.
42

2) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (3-carboxypropyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3 -Dihydro-2H-1,4-benzodiazepin-2-one (IV-70) ester (IV-69) (940 mg, 1.425 m)
M) was dissolved in methanol (25 ml) and dichloromethane (5 ml). Dichloromethane is distilled off and 10%
An aqueous sodium hydroxide solution (4 ml) was added. The solution was stirred at room temperature for 3 hours. Ice water was added and the mixture was concentrated to half volume. 10% hydrochloric acid (6 ml) was added, and the solid matter was collected by filtration and dried to obtain 845 mg (91.8%). IRνmax (KBr): 3320, 1675, 164
0,1611 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.86 (2H,
qui, J = 7 Hz), 2.31 (3H, s), 2.3
7 (2H, t, J = 8 Hz), 3.49 (2H, t, J
= 7 Hz), 3.51 (3H, s), 3.57 (8H,
br. s), 4.53 (2H, s), 5.56 (1H,
s), 6.83 (1H, m), 7.07-7.50 (1
0H, m), 7.69 (1H , m) Elemental analysis _{(C 34 H 39 N 5 O} 8 0.8H 2 O as) Found: C, 61.86; H, 6.16 ; N, 10.
69 Calculated: C, 61.86; H, 6.20; N, 10.
61

3) Compound (IV-71) Coupling was carried out in the same manner as in Example 1 to give compound (IV-7)
1) was obtained with a yield of 81.4%. mp = 119-122 ° C. (MeOH) IRνmax (kBr): 3320, 1650, 161
0 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.86 (2H,
qui, J = 7 Hz), 2.26 (2H, t, J = 8H)
z), 2.30 (3H, s), 2.60 (2H, t, J
= 7 Hz), 3.30-3.65 (12H, m), 3.
48 (3H, s), 3.62 (2H, s), 4.52
(2H, s), 5.48 (1H, s), 6.55 (1
H, s), 6.83 (1H, m), 6.98-7.47.
(10H, m), 7.63 ( 1H, m) Elemental analysis _{(C 41 H 50 N 10 O} 7 S 2 H 2 as O) Found: C, 56.21; H, 5.97 ; N, 16 .
18; S, 7.07 Calculated: C, 56.15; H, 5.98; N, 15.
97; S, 7.31 hydrochloride (as C ₄₁ H ₅₀ N ₁₀ O ₇ S ₂ 1.3 HCl H ₂ O) Found: C, 53.10; H, 5.94; Cl, 5.
04; N, 15.17; S, 7.07 Calculated: C, 53.27; H, 5.81; Cl, 4.
99; N, 15.15; S, 6.91

Example 14 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propyloxy) ethoxy) ethylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-72) and its hydrochloride

Embedded image The compound was coupled in the same manner as in Example 2 to give compound (IV-7)
2) was obtained with a yield of 85.1%. IRνmax (KBr): 3300, 1670, 164
0.11610 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m);
60 (4H, m), 1.85-2.06 (4H, m),
2.29 (3H, s), 2.34 (2H, t, J = 8H)
z), 2.42 (4H, m), 3.44 (3H, s),
3.47 (12H, br.s), 3.55 (2H,
s), 4.00 (2H, t, J = 6 Hz), 4.49
(2H, s), 5.54 (1H, d, J = 8 Hz),
6.54 (1H, m), 6.68-7.48 (17H,
m), 7.58 (1H, m), 7.95 (1H, br.
s) Elemental analysis _{(C 49 H 61 N 7 O} 8 0.8H 2 as O) Found: C, 66.13; H, 7.01 ; N, 11.
07 Calculated: C, 66.09; H, 7.09; N, 11.
01 hydrochloride (as C ₄₉ H ₆₁ N ₇ O ₈ HCl H ₂ O) Found: C, 63.10; H, 6.84; Cl, 3.
74, N, 10.62 Calculated: C, 63.25; H, 6.93; Cl, 3.
81; N, 0.54

Example 15 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) methoxy) ethoxy) ethylpiperazinocarbomethoxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-7
3)

Embedded image The compound was coupled in the same manner as in Example 2 to give compound (IV-7)
3) was obtained with a yield of 72.7%. IRνmax (KBr): 3345, 1660, 161
0,1599 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m);
59 (4H, m), 1.99 (2H, qui, J = 6H
z), 2.29 (3H, s), 2.33-2.64 (1
0H, m), 3.43 (3H, s), 3.47 (2H,
s), 3.47 (2H, s), 3.49-3.75 (1
3.H (2H, m), 3.99 (2H, t, J = 6Hz), 4.
03 (2H, s), 4.67 (1H, d, J = 13H
z), 4.74 (1H, d, J = 13 Hz), 5.55
(1H, d, J = 8 Hz), 6.70-6.94 (4
H, m), 6.98-7.41 (13H, m), 7.5.
8 (1H, m), 7.70 (1H, s) Elemental analysis _{(C 51 H 64 N 8 O} 8 H 2 O as) Found: C, 65.42; H, 7.17 ; N, 12.
30 Calculated: C, 65.51; H, 7.11; N, 11.
98 hydrochloride IRνmax (KBr): 3400, 3300, 166
7,1640,1608,1599 cm ^-1 elemental analysis (C ₅₁ H ₆₄ N ₈ O ₈ 2.1 HCl · 1.8H ₂
Found: C, 59.55; H, 6.83; N, 11.
11; Cl, 7.20 Calculated: C, 59.70; H, 6.85;
92; Cl, 7.26

Example 16 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(2- (2- (guanidino-1,3-thiazole-4-
Yl) methylthio) ethylcarbamoyl) methoxy) ethoxy) ethylpiperazinocarbomethoxyphenyl)-
1,3-dihydro-2H-1,4-benzodiazepine-
2-one (IV-74)

Embedded image Coupling was carried out in the same manner as in Example 1 to give compound (IV-7)
4) was obtained with a yield of 65.3%. IRνmax (KBr): 3320, 1650, 160
0 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H, s),
2.49 (4H, m), 2.58 (2H, t, J = 6H
z), 2.66 (2H, t, J = 7 Hz), 3.37 −
3.66 (12H, m), 3.48 (3H, s), 3.
62 (2H, s), 3.98 (2H, s), 4.73
(2H, s), 5.50 (1H, s), 6.46 (1
H, s), 6.82 (1H, m), 7.01-7.48.
(10H, m), 7.62 ( 1H, m) Elemental analysis _{(C 43 H 53 N 11 O} 7 S 0.7H 2 O as) Found: C, 56.61; H, 6.01 ; N, 16.
84; S, 6.89 Calculated: C, 56.59; H, 6.01; N, 16;
88; S, 7.03 hydrochloride IRνmax (KBr): 3300, 1660, 160
0 cm ^-1 elemental analysis (C ₄₃ H ₅₃ N ₁₁ O ₇ S ₂ 2.2 HCl 1.8
H ₂ O as) Found: C, 51.14; H, 5.92 ; Cl, 7.5
N; 15.14; S, 6.39 Calculated: C, 51.00; H, 5.85; Cl, 7.7.
0; N, 15.21; S, 6.33

Example 17 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (2-
(2- (N'-cyano-N "-(3- (3- (piperidinomethyl) phenoxy) propyl) guanidino) ethoxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4- Benzodiazepin-2-one hydrochloride (IV-79)

Embedded image The compound was coupled in the same manner as in Example 2 to give compound (IV-7)
9) was obtained with a yield of 69.6%. IRνmax (KBr): 3310, 2160, 167
0,1642,1580 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
74 (4H, m), 1.90 (2H, quint, J =
5.8 Hz), 2.29 (3H, s), 2.65 (4
H, br. s), 3.24 (2H, m), 3.30-
3.85 (14H, m), 3.43 (3H, s),
98 (2H, t, J = 5.9 Hz), 4.51 (2H,
s), 5.51 (1H, d, J = 7.8 Hz), 5.9
8 (1H, t, J = 5.6 Hz), 6.23 (1H, b
r. s), 6.75-5.90 (3H, m), 6.92.
−7.03 (2H, m), 7.06-7.42 (11
H, m), 7.47 (1H, d, J = 7.8 Hz),
7.59 (1H, m), 8.28 (1H, br.s) elemental analysis _{(C 49 H 6 0N 10 O} 7 1.5H 2 O as) Found: C, 63.52; H, 6 . 86; N, 15.2
5 Calculated: C, 63.52; H, 6.87; N, 15.0.
9

Example 18 1-methyll-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (N′-
Cyano-N "-(3- (3- (piperidinomethyl) phenoxy) propyl) guanidino) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-80)

Embedded image Coupling was carried out in the same manner as in Example 2 to give compound (IV-8)
0) was obtained with a yield of 62.1%. IRνmax (KBr): 3320, 2160, 167
5,1580 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.49 (2H,
m), 1.67 (4H, m), 2.01 (2H, qu)
i, J = 6 Hz), 2.30 (3H, s), 2.55
(4H, br.s), 3.20-3.45 (6H,
m), 3.48 (3H, s), 3.61 (2H, br.
s), 4.03 (2H, t, J = 6 Hz), 4.50.
(2H, s), 5.48 (1H, s), 6.79-6.
95 (3H, m), 6.99-7.47 (12H,
m), 7.63 (1H, m ) Elemental analysis _{(C 45 H 52 N 10 O} 5 1.5H 2 O as) Found: C, 64.12; H, 6.46 ; N, 16.
82 calc: C, 64.34; H, 6.60; N, 16.
68

Example 19 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (4- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-3-enyl) piperazinocarbomethoxy) phenyl) -1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-177)

Embedded image 1) N-Boc-N '-(3- (2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-3-enyl) piperazine (IV-
175) Coupling as above, compound (IV-175)
Was obtained with a yield of 45.4%. NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.
39 (4H, t, J = 9.4 Hz), 2.71 (2H,
t, J = 6.4 Hz), 3.12 (2H, d, J = 6.
0 Hz), 3.43 (6H, m), 3.65 (2H,
s), 6.47 (1H, d, J = 15.6 Hz), 6.
44 (1H, s), 6.78 (1H, dt, J = 15.
2,6.2 Hz)

2) Compound (IV-177) The Boc-protected compound (IV-175) obtained in 1) was treated with 4N hydrochloric acid in ethyl acetate to give an amine hydrochloride (IV-1).
76) was obtained. Next, coupling was performed in the same manner as described above to obtain compound (IV-177) at a yield of 37.6%. NMR (CDCl ₃ + CD ₃ OD) δ: 2.28 (3H,
s), 2.3-2.5 (8H, m), 2.71 (2H,
t, J = 6.4 Hz), 3.05 (2H, m), 3.4
-3.7 (6H, m), 3.47 (3H, s), 3.6
4 (2H, s), 4.75 (2H, s), 5.50 (1
H, s), 5.93 (1H, d, J = 15.2 Hz),
6.51 (1H, s), 6.71 (1H, dt, J = 1)
5.2, 6.6 Hz), 6.81 (1H, m), 6.9
5-7.5 (10H, m), 7.62 (1H, m) dihydrochloride IRνmax (nujol): 3280,1672,1
638, 1610, 1555 cm ^-1 elemental analysis (as C ₄₁ H ₄₉ N ₁₁ O ₅ S ₂ Cl ₂ 1.4H ₂ O) Found: C, 52.61; H, 5.58; N, 16.2
N, 9; S, 6.54; Cl, 7.94 Calculated: C, 52.60; H, 5.58; 16.4
6; S, 6.85; Cl, 7.57

Example 20 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-2-enylpiperazino) ethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-203)

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3-hydroxyphenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-197) Starting from m-anisaldehyde, Sugasawa et al. [T. Sugasawa, M .; Adachi and
K. Sasakara, J .; Heterocyclic
c. Chem. , 16 , 445 (1979)] and a benzodiazepine skeleton produced by the method of Bock et al. [M. G. FIG. Bock, R.A. M. Di Pardo, B .;
E. FIG. Ejans. K. E. FIG. Rittle, D .; F. Ve
ber, R .; M. Freidinger, J. et al. Hirs
hfield and J.H. P. Springer,
J. Org. Chem. 52 , 3232 (1987)]
1-methyl-3- (N '-(m-
Tolyl) ureido) -5- (3-anisyl) -1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-196) (428 mg) in dichloromethane (25
ml) in a nitrogen atmosphere.
(3 ml) in dichloromethane (5 ml) was added dropwise at -20 ° C. The mixture was stirred at −20 ° C. for 8 hours and poured into ice-water. The mixture was extracted with dichloromethane-methanol.
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel (30 g) and chloroform:
Recrystallization from ethyl acetate by chromatography with methanol (20: 1) gave compound (IV-19).
7) 282 mg (68.1%) were obtained.

2) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-tetrahydropyranyloxy) ethoxyphenyl-1,3-dihydro-2H
-1,4-benzodiazepin-2-one (IV-19
8) A mixture of compound (IV-197) (3.0 g), 2-tetrahydroxyethyl bromide (3.02 g) and potassium carbonate (5.03 g) in acetonitrile (50 ml) was heated under reflux for 18 hours. Add water, filter solids,
The extract was washed with water, dried and recrystallized from ethyl acetate to give compound (IV)
-198), 2.0 g (50.9%). mp = 118-122 ° C. 3) 1-methyl-3- (N ′-(m-tolyl) ureido) -5- (3- (2-hydroxy) ethoxyphenyl-1,3-dihydro-2H-1,4 -Benzodiazepin-2-one (IV-199) Compound (IV-198) (2.00 g) and p-toluenesulfonic acid (0.15 g) in methanol (20 ml)
The solution was heated at reflux for 4 hours. An aqueous solution of sodium hydrogen carbonate was added, and the solid matter was collected by filtration, washed with water, dried and recrystallized from ethyl acetate to give 1.50 g of the compound (IV-199) (88.
8%). mp = 156-158 ° C

4) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-methanesulfonyloxy) ethoxyphenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-200) A solution of methanesulfonyl chloride (603 mg) in dichloromethane (10 ml) was added to compound (IV-199) (1.20).
A solution of 8g) in dimethylformamide (15ml), triethylamine (4ml) and dichloromethane (20ml) was added dropwise at -20 ° C. The solution was stirred at −20 ° C. for 1 hour, poured into dilute hydrochloric acid and extracted with dichloromethane: methanol. The extract was washed with water and concentrated under reduced pressure. Water was added, the solid was collected by filtration, washed with water, and dissolved in dichloromethane: methanol. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crystalline residue was washed with benzene and dried to obtain 1.27 g (89.8%) of compound (IV-200).

5) Compound (IV-203) Compound (IV-200) (225 mg), compound (IV-176) (230 mg) obtained in Example 19 and potassium carbonate (2.5 g) in acetonitrile (5 ml) The mixture was heated at reflux for 20 hours. Dichloromethane: methanol was added, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was silica gel (30 g), chloroform: methanol: ammonium hydroxide (5: 1: 0.125).
The compound (IV-2)
03) 120 mg (34.7%) were obtained. NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.55 (4H, br.s), 2.62 (6H,
br. s), 2.70 (2H, t, J = 6.7 Hz),
2.83 (2H, t, J = 5.6 Hz), 3.12 (2
H, d, J = 5.4 Hz), 3.45 (2H, t, J =
5.6 Hz), 3.48 (3H, s), 3.65 (2
H, s), 4.14 (2H, t, J = 5.6 Hz),
5.50 (1H, s), 5.95 (1H, d, J = 1
5.4 Hz), 6.47 (1H, s), 6.7-6.9
(2H, m), 7.02 (2H, m), 7.1-7.5
(8H, m), 7.62 (1H, m) 0.1-N hydrochloric acid (4.2 ml) was added to the residue. Methanol was added until the solids dissolved and the volatiles were distilled off under reduced pressure. IRνmax (nujol): 3280, 1676, 160
5,1554 cm ^-1 elemental analysis (C ₄₁ H ₄₉ N ₁₁ S ₂ O ₄ 3HCl 1.1H ₂
Found: C, 51.53; H, 5.70; N, 16.2
Cl; 11.44; S, 6.89 Calculated: C, 51.66; H, 5.73; N, 16.1
6; Cl, 11.16; S, 6.73

Example 21 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (2- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) propylpiperazino) ethoxy) phenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-204)

Embedded image Compound (IV-204) was obtained in a yield of 11.1% in the same manner as in Example 20 above. NMR (CDCl ₃ ) δ: 1.80 (2H, m), 2.
26 (3H, s), 2.2-2.9 (16H, m),
3.42 (2H, t, J = 6.5 Hz), 3.43 (3
H, s), 3.60 (2H, s), 4.14 (2H,
m), 5.54 (1H, d, J = 8.0 Hz), 6.3
8 (1H, s), 6.8-7.7 (12H, m) hydrochloride IRνmax (nujol): 3280,16790,16
05, 1554 cm ^-1 elemental analysis (C ₄₁ H ₅₁ N ₁₁ O ₄ S ₂
3.3HCl 0.9H As ₂ O) Found: C, 51.32; H, 6.00 ; N, 15.8
9; Cl, 12.10; S, 6.65 Calculated: C, 51.16; H, 5.87; N, 16.0
1; Cl, 12.15; S, 6.66

Example 22 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (3- (2-
(2- (guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) propylcarbamoyloxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-226)

Embedded image 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-benzyloxycarbonyl) propylcarbamoyloxy) phenyl) -1,3-dihydro-2H-1,4 -Benzodiazepin-2-one (I
V-223) Phenyl derivative (IV) in dichloromethane (30 ml)
-197) (708 mg), 3- (benzyloxycarbonyl) propyl isocyanate (905 mg) and a few drops of triethylamine were stirred at room temperature for 2 days. Volatile materials were distilled off under reduced pressure. The residue was purified on silica gel (50
g) and chloroform: methanol (20: 1) to give compound (IV-22)
3) 1.19 g (quantitative) were obtained. It was again subjected to silica gel chromatography with ethyl acetate: hexane (2: 1).

2) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-carboxypropylcarbamoyloxy) phenyl) -1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-2
24) A mixture of the ester (IV-223) (0.98 g) and 5% palladium / C (230 mg) in methanol (20 ml) and ethyl acetate (10 ml) was added in the presence of hydrogen for 30 minutes.
Stirred for minutes. The catalyst was filtered and washed with methanol.
The filtrate was concentrated under reduced pressure, and 0.72 g of compound (IV-224) was obtained.
(85.7%). 3) Compound (IV-226) Compound (IV-226) was coupled in the same manner as in Example 2 above.
226) 40 mg (24.9%) were obtained. IRνmax (nujol): 3330, 1696, 165
0,1603,1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.82 (2H,
qui, J = 7.0 Hz), 2.20 (2H, t, J =
7.2 Hz), 2.42 (3H, s), 2.67 (2
H, t, J = 6.7 Hz), 3.2-3.4 (4H,
m), 3.44 (3H, s), 3.64 (2H, s),
5.32 (1H, s), 6.44 (1H, s), 6.8
5-7.0 (2H, m), 7.1-7.5 (9H,
m), 7.62 (1H, m ) Elemental analysis _{(C 36 H 40 N 10 O} 5 S 2 1.2H 2 O as) Found: C, 55.61; H, 5.51 ; N, 17. 9
3: S, 8.13 Calculated: C, 55.54; H, 5.49; N, 17.9
9; S, 8.24

Example 23 1-methyl-3- (N'-
(M-tolyl) ureido) -5- (3- (5- (5-
(3- (3- (piperidinomethyl) phenoxy) propylamino) thia-3,4-diazol-5-yl) pentylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-230)

Embedded image 1) 2- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (3-carbomethoxy) propylamide) thia-3,4-diazole (IV-22)
7) 4-carbomethoxybutyric chloride (350 mg, 2.13
mM) in dichloromethane (5 ml).
219) (513 mg, 1.476 mM) and triethylamine (1 ml) in dichloromethane (20 ml). The solution was stirred at room temperature for 5 hours, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on silica gel (4
0 g) and chloroform: methanol (10: 1), which is separated from dichloromethane: ether and solidified as compound (IV-227).
550 mg (78.3%) were obtained.

2) 2- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (5-hydroxypentylamino) thia-3,4-diazole (IV
-228) Amide (IV-227) (527 mg, 1.108 mM) and lithium aluminum hydride (85 mg, 2.239 mM)
The mixture of M) in tetrahydrofuran (20 ml) was stirred at room temperature for 2 hours and heated at reflux for 3 hours. Ethyl acetate and then brine were added under ice cooling. The insoluble material was filtered and extracted with chloroform: methanol (9: 1). The filtrate was concentrated under reduced pressure, and the residue was subjected to chromatography using silica gel (20 g) and chloroform: methanol (10: 1 to 7: 1) to obtain 392 mg of compound (IV-228).
(83.9%).

3) 2- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (5-azidopentylamino) thia-3,4-diazole (IV-2)
29) The above alcohol (IV-228) (392 mg, 0.93)
To a solution of 0 mM) in tetrahydrofuran (5 ml) was added a solution of 0.5 M hydrazonic acid in benzene (2 ml) and triphenylphosphine (270 mg, 1.03 mM). Diethyl azodicarboxylate (180mg, 1.03m
A solution of M) in tetrahydrofuran (1 ml) was added under ice cooling. The mixture was stirred at room temperature for 20 hours. Volatile substances were distilled off under reduced pressure. The residue was chromatographed on silica gel (40 g), chloroform: methanol (10: 1) to give 222 mg of compound (IV-229)
2.2%) as an oil. 4) Compound (IV-230) A mixture of azide (IV-229) (222 mg, 0.486 mM) and 5% palladium / C (100 mg) in methanol (2.5 ml) was stirred in the presence of hydrogen for 20 hours. The catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue (186 mg, 89.0%) and carboxylic acid (IV-9) (250 mg, 0.529 mM) were treated in the same manner as described above to give compound (IV-230) 160 mg (41.
8%). IRνmax: 3374, 3343, 1670, 160
1,1555,1516 cm ^-1 NMR (CDCl ₃ ) δ: 1.16 (2H, qui, J
= 6.9 Hz), 1.45 (6H, m), 1.62 (4
H, m), 2.03 (2H, qui, J = 6.2H)
z), 2.26 (3H, s), 2.46 (4H, m),
3.10 (2H, q, 6.6 Hz), 3.27 (2H,
m), 3.43 (5H, s), 3.51 (2H, s),
4.02 (2H, t, J = 6.0 Hz), 4.47 (1
H, d, J = 15.0 Hz), 4.52 (1H, d, J)
= 15.0 Hz), 5.41 (2H, m), 5.58
(1H, d, J = 8.2 Hz), 6.62 (1H, t,
J = 5.8 Hz), 6.71-7.43 (5H, m),
7.58 (1H, m), 7.88 (1H, d, J = 8.
2 Hz), 8.10 (1 H, s) Elemental analysis (as C ₄₈ H ₅₈ N ₁₀ O ₅ S 0.9 H ₂ O) Found: C, 63.82; H, 6.71; N, 15.3
8; S, 3.56 Calculated: C, 63.82; H, 6.67; N, 15.5
1; S, 3.55

EXPERIMENTAL EXAMPLE 1 The pharmacological effects of the compounds prepared in the above Examples were evaluated by antagonizing the gastrin receptor using guinea pig gastric mucosa, and using the mouse cerebral cortex CCK receptor (CCK-B receptor) and pancreas. In vitro, two items of antagonism to the CCK receptor (CCK-A) were examined in vitro.

Experimental animals : Male Sprague Dawley rats (weight 220-270 g), male Hartley guinea pigs (weight 450-600 g), or male ddY mice (weight 24-30 g) were used. Drug: L-365,26 as gastrin receptor antagonist
0 (the compound described in Example 281 of JP-A-63-238069), and others were commercially available.

(1) Preparation of In Vitro Gastrin Receptor Antagonizing Gastric Glands: Male Hartley guinea pigs (weight 450-600
After sacrifice and killing of g), immediately remove the stomach, cut out the greater curvature, and wash the contents in cold water. 2. Krebs Bicarb solution (Krebs Bicarb solution)
onate Solution) (ice-cooled), gently wipe the mucus with absorbent cotton soaked with 1M NaCl (ice-cooled), and wash with Krebs solution. 3. The mucous membrane surface is gently wiped with absorbent cotton soaked with Krebs solution, the mucous membrane is peeled off using a slide glass, added to a Hank's Balanced Solt Solution containing 0.1% BSA, and washed.

4. 0.1 dissolved in Hank's solution on detached mucosa
% Collagenase solution and incubate at 37 ° C for 20 minutes with intermittent gentle shaking. The supernatant was decanted, and a fresh 0.1% collagenase solution was added.
Incubate for another 20 minutes. 5. Aspirate and discharge 3-4 times using a 20 ml syringe to separate cells (5-10 cells are adhered gastric glands instead of isolated cells) and filter (200 nylon mesh). . After centrifugation at 6.270 × g (1000 rpm) for 3 minutes, the supernatant is discarded, 0.2% neutral protease (EC 3.4.24.) Dissolved in Hank's solution is added, and the mixture is incubated at 37 ° C. for 15 minutes. After centrifugation at 7.270 × g (1000 rpm) for 3 minutes, the supernatant is discarded, Krebs solution containing 0.1% BSA and 25 mg / 100 ml bacitracin is added, and the cells are washed by pipetting in the same manner. Repeat three times. All the above operations are performed under 95% CO ₂ -5% O ₂ aeration. 8. Count the number of viable cells. An equivalent volume of 0.4% trypan blue (trypan blue) is added to 50 μl of the cell solution, and the cells are shaken gently to stain dead cells, and then the number of viable cells is counted. Dilute to 10 ⁶ cells / ml with incubation medium, seal and keep on ice until use.

Binding Assay a) Preparation of Test Compound Approximately 2 mg was weighed into each 20 ml glass vial,
Dissolve in DMSO solution to make 1 mM concentration. Next, 250 μM (final concentration: 10 μM) is diluted with a 50% DMSO solution to prepare a tube. Further, each 1/10 concentration is diluted to 25 nM (final concentration 1 nM). In a tube, 10 μl of the test compound, [ ¹²⁵ I] gastrin (5 n)
M) Add 10 μl and 230 μl of cells (10 ⁶ cells / ml). After incubation at 25 ° C for 30 minutes,
Centrifuge at 3000 rpm for 5 minutes and aspirate the supernatant. Add 0.5 ml of ice-cooled Krebs solution, mix gently, and immediately centrifuge to remove the supernatant by suction. Radioactivity is measured with a gamma counter. The total number of bonds was measured in the same manner using 10 μl of a 50% DMSO solution instead of the test compound, and the non-specific number of bonds was measured using 10 μl of human gastrin I (50 μM). e) Calculation of IC _50: IC _50; specific binding number of the test compound (total binding count (cpm) one non-specific bound counts (cpm))
Was calculated.

(2) Preparation of in vitro CCK-A and -B receptor antagonist CCK receptor preparation: male ddY mouse (body weight 24 to
After decapitation and sacrifice of 30 g), the cerebral cortex (CCK-B) and pancreas (CCK-A) were immediately removed. Preparation of receptor specimen (crude membrane fraction): The mice are sacrificed by decapitation, the cerebrum and pancreas are immediately removed, washed with a pre-cooled PBS solution, and the cerebrum is separated from the cortex. 2. The cerebral cortex and pancreas were treated with 50 mM Tris buffer (p
H7.4, cool) again. 3. Weigh each to 1.5-2.0 g / vial and store at -80 ° C until use.

4. Add a 10-fold amount of 50 mM Tris buffer, homogenize with a Teflon-glass homogenizer (7 strokes), and homogenize with a Polytron homogenizer for 20 seconds. 5. Centrifuge at 40,000 xg for 15 minutes to obtain a pellet. 6. Add a 10-fold volume of 50 mM Tris buffer, homogenize with a Polytron homogenizer for 20 seconds, and centrifuge similarly to obtain a pellet (repeated twice, measuring the amount of protein). 7. 10 volumes of 10 mM incubation buffer
HEPES, 130 mM NaCl, 4.7 mM KC
1, 5 mM MgCl ₂ .6H ₂ O, 1 mM EGTA,
5 mg / ml BSA and 0.25 mg / ml bacitrosin) and added with a Polytron homogenizer.
After homogenizing for 2 seconds, the cerebral cortex was finally diluted 40 times and the pancreas was diluted 200 times with the same buffer.
B and CCK-A receptor specimens.

Displacement assay a) Preparation of test compound Approximately 2 mg was weighed into each 20 ml glass vial,
Dissolve in DMSO solution to make 1 mM concentration. Then, using a Shionogi tube, 250 μM with 50% DMSO solution
(Final concentration 10 μM) to make dilution. Furthermore, 1/10
Make dilutions for each concentration to 25 nM (final concentration 1 nM).
20 μl of the test compound in a tube, [ ³ H] CCK-8
Add 10 μl (50 nM) and 470 μl receptor sample. After incubation at 25 ° C. for 90 minutes, the mixture is suction-filtered (Whatman glass microfilter, GF / C) and washed three times with cold 50 mM Tris buffer. 5
Add ml of Aquasol-2 Kactyl, leave for several hours after shaking and count the radioactivity for 5 minutes. The total number of bonds was measured using 20 μl of a 50% DMSO solution instead of the test compound.
For the measurement of the number of non-specific binding, cerulein
The same procedure was performed using 20 μl (25 nM). e) IC ₅₀ IC ₅₀ : number of specific bonds of test compound (total number of bonds (dpm)
One non-specific binding number (dpm)) was calculated and determined. The results are summarized in Tables 1 and 2 below.

Experimental Example 2 PA ₂ was determined by the following method, and the histamine H ₂ receptor antagonism in vitro was examined. Male Hartley guinea pigs (body weight 450-600 g) were exsanguinated and killed, the right atrium was excised, and a Magnus apparatus (Krebs bicarbonate buffer aerated with 95% O ₂ and 5% CO ₂ , 30 ° C.).
Hanged up. The chronotropic effect was examined by cumulatively administering this device histamine. The calculation of pA ₂ , a parameter of histamine H ₂ receptor antagonism, was determined as the negative logarithm of the antagonist required to translate the histamine dose-response curve by a factor of 2 toward the higher concentration side [ Kazunari Takayanagi Basic course of drug development V (Kyosuke Tsuda, edited by Hisashi Nogami,
Jinjinkan) p731-776, Tokyo (1974) and Van Rossum J.
M., Arch.Int.Pharmacodyn.Ther. 143: 299-330 (196
3)]. Table 2 shows the results.

[0094]

[Table 1]

[0095]

[Table 2]

[0096]

[Table 3]

[0097]

[Table 4]

Embedded image

Experimental Example 3 In this experimental example, in order to demonstrate the usefulness of the benzodiazepine derivative of the present invention, a combination of a histamine H ₂ receptor antagonist (H ₂ B) and a compound having a gastrin receptor antagonistic action was prepared. The effect of reducing or preventing ulcer recurrence was examined based on the increase in gastric acid secretion (rebound effect), which is said to lead to ulcer recurrence after continuous administration and withdrawal of the ulcer, and the resistance of the gastric mucosa after the withdrawal.

Experimental Materials Male Sprague Dawley rats (body weight 2) were used as experimental animals.
40-280 g). Famotidine as H ₂ B and L-365,260 as gastrin receptor antagonist
Was used. The mixture was famotidine (molecular weight: 337.
Since 4) and L-365,260 (molecular weight 398.44) have almost the same molecular weight, they were prepared at a mixing ratio of 1: 1. For administration, famotidine and L-365,260 include 1
0 mg was used by suspending in 1 ml of vehicle (vehicle: 0.5% methylcellulose solution). The mixture is a mixture of equal amounts of each suspension.

Administration Method A dose (1.0 ml or 3.0 ml / kg) of each test substance is put into a syringe, and a stainless steel oral sonde needle fitted with this is attached.
(φ1.2 × L80 mm) was directly inserted into the stomach from the mouth of the rat and gavage administration was performed. Experimental method A. Single administration experiment (1) Water immersion restrained stress gastric injury (Single administration experiment) Rats fasted for 24 hours (however, water intake is free) (body weight 27)
0-290 g) was orally administered with a test compound, and 30 minutes later, a stress was applied by the following method. That is, the rats were placed in a medicinal type stress cage (manufactured by Natsume Seisakusho), immersed in a 23 ° C. water tank to the height of the thrust ridge, and subjected to stress [Takagi Chem. Pharm. Bull (Tokyo)
12 465-472 (1964)]. Seven hours later, the rats were pulled out of the water tank and killed with ether, and the stomach was removed. The isolated stomach was injected with 13 ml of 1% formalin solution into the stomach, immersed in the same concentration of formalin solution for 10 minutes, and fixed. The stomach was incised along the greater curvature and stretched on a glass plate (hereinafter abbreviated as formalin treatment). The major axis (mm) of each lesion (hemorrhagic erosion) generated in the glandular stomach was measured under a dissecting microscope (× 10).

B. Continuous administration experiment: (A) Vehicle (0.5% methylcellulose solution) administration group (1 ml / kg) (B) Famotidine 10 mg / kg / day continuous administration group (famotidine 10 mg suspended in 0.5% methylcellulose 1 ml) Or Famotidine 30 mg / kg / day administration group (C) L-365,260 10 mg / kg / day continuous administration group (D) (Famotidine + L-365,260) 10 mg / k each
g / day combination drug administration group

(2) Basal acid secretion after drug withdrawal by continuous administration of famotidine Famotidine 10 or 30 mg was administered to rats reared normally.
/ Kg once a day for 1 week. After the last dose
Basal gastric acid secretion (total acid excretion) at the time of withdrawal is 10 mg /
The pylorus ligation was performed immediately after the final administration, 24 hours and 48 hours (2 days) after the last administration for the kg / day continuous administration group, and 3 days and 4 days after the final administration for the 30 mg / kg / day continuous administration group, respectively. (4 hour method) [Shay H.
Gastroenterology, 5 43-61 (1945)] was measured in. That is, the rat was opened under ether anesthesia and the pylorus was ligated. Four hours later, the stomach was removed again under ether anesthesia, and the stored gastric juice was collected. Gastric juice is centrifuged (30
00 rpm. After 10 minutes), the pH and the acidity were measured.
The acidity was titrated with N / 10 NaOH to pH 7.0. The total acid secretion (μEq / 4 hours) as the product of each acidity and liquid volume
Was calculated.

(3) Aspirin-induced gastric mucosal injury to gastric mucosa after continuous administration of famotidine 200 mg / kg of aspirin was orally administered to rats on the second day after the continuous administration of famotidine. Seven hours later, the stomach was removed under ether anesthesia, treated with 1% formalin solution, and the length (mm) of gastric mucosal injury generated in the glandular stomach was measured. The rats were fasted for 24 hours before aspirin administration (however, water was freely available).

Experimental results (1) Gastric injury due to water immersion restraint stress

[Table 5] Any dose of L-365,260 (1 or 3 mg / kg)
Nor did it suppress the development of stress gastric injury. A dose of 3 mg / kg of famotidine was significantly suppressed. The combination group showed a stronger inhibitory effect than the single agent at any dose (Table 3).
reference).

(2) Basal acid secretion after drug withdrawal by continuous administration of famotidine

[Table 6]

[0106]

[Table 7]

[0107]

[Table 8]

In the group of continuous administration of famotidine (10 mg / kg / day), the basal gastric acid secretion was significant immediately after the drug was stopped (P <0.0).
5), and significant (P <0.05) 48 hours after withdrawal
Severe enhancement was observed. Famotidine (30m
g / kg / day) In the continuous administration group, basal gastric acid secretion immediately after withdrawal was significantly (P <0.05) suppressed, but 4 days after withdrawal, significant (P <0.05) enhancement was observed. (See Tables 4, 5, and 6).

[0109]

[Table 9] On the other hand, the blood gastrin level increased significantly (P <0.05) as compared with the control group immediately after the end of continuous administration, due to the suppression of acid excretion. Until the day, there was almost no difference from the control group. Famotidine 10 mg / kg / day continuous administration increased acid excretion after withdrawal was due to famotidine (10 mg / kg) and L-365,
By mixing with 260 (10 mg / kg), an increase in the amount of acid excreted tended to be suppressed. In addition, in the acid excretion amount, there was no difference between the control group and the L-365,260 alone administration group for one week (see Table 7).

(3) Aspirin-induced gastric mucosal injury to gastric mucosa after continuous administration of famotidine

[Table 10] A number of linear disorders caused by aspirin occurred in the stomach. As is clear from the table, the famotidine continuous administration group was
The group showed a significant (P <0.05) deterioration as compared with the control group, and the group administered with the combination of famotidine and L-365,260 suppressed this significantly (P <0.05). In addition, L-365,26
The 0 consecutive administration group showed a tendency to worsen, but was not significant.

After continuous administration of famotidine and withdrawal (day 2), enhancement of basal acid secretion (acid rebound) was observed.
This is considered to be a common phenomenon of H ₂ B. Further, when the reactivity of the gastric mucosa of the group of continuous administration of famotidine to aspirin gastric mucosal injury was examined, the ulcer index significantly deteriorated on the second day of drug withdrawal. This is consistent with the point at which acid rebound was noted above. This suggested that famotidine treatment weakened the defense mechanism of the gastric mucosa. Furthermore, the exacerbating effects of acid rebound and aspirin gastric mucosal injury by famotidine are shown in L-365,260.
It was clarified that it can be suppressed by using a mixture with These results generally indicate that gastric damage after H ₂ B ulcer treatment can be prevented by combination use with gastrin receptor antagonists (see Table 8). The above results strongly suggest that the benzodiazepine derivative of the present invention is useful as an anti-ulcer therapeutic agent which is not accompanied by recurrence of ulcer after treatment or whose recurrence is reduced.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Yasunobu Ishihara 61 Nishikujo-harikoji-cho, Minami-ku, Kyoto-shi, Kyoto

Claims (7)

(57) [Claims] 1. Formula I: ## STR1 ## Wherein R ¹ and R ³ are each independently hydrogen, halogen, lower alkyl or lower alkyloxy; R ² is hydrogen or lower alkyl; R ⁴ is a single bond or —CO—;
R ⁵ is an aliphatic heterocyclic ring or —NH—; R ⁶ is an optionally substituted C ₁ -C ₁₅ alkylene or an optionally substituted C ₂ -C ₁₅ alkenylene (provided that The alkylene and alkenylene may be substituted within the groups themselves and / or between those groups and adjacent groups by
One or more groups selected from S and NH may be interposed); R ⁷ is any of the following groups: Embedded image Embedded image Embedded image A benzodiazepine derivative or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R ¹ is hydrogen and R ² and R ³ are both lower alkyl. 3. The compound according to claim 1, wherein said aliphatic heterocycle is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or dioxanyl. 4. The method according to claim 1, wherein the alkylene is-(CH ₂ CH ₂ R ⁸ ) p
(CH ₂ ) qR ⁹ (CH ₂ ) r- (wherein R ⁸ and R
⁹ is each independently a single bond, O, S or NH; p
Is an integer of 0 to 5; q is an integer of 1 to 3; r is an integer of 0 to 2). 5. The compound according to claim 4, wherein R ⁸ is O, p is 2 or 3, and R ⁹ is a single bond. 6. The method according to claim 1, wherein said alkenylene is-(CH ₂ -C
^{(R 10) = CH) q-} ( wherein, R ¹⁰ is hydrogen, hydroxy, methyl, or halogen,; q compound of claim 1 is a group represented by from 1 represents an integer of 3). 7. An anti-ulcer agent comprising the compound according to claim 1.